Metabolic Syndrome: Introduction

Metabolic Syndrome: Overview

- Syndromes refers to signs and symptoms which are correlated with each other and
often associated with a particular disease of disorder.
- Metabolic Syndrome: a cluster of risk factors for cardiovascular disease and type 2
diabetes mellitus, which occur together more often by chance alone.
- Significance of Risk Factors
o Raised blood pressure
o Dyslipidaemia (raised triglycerides and lowered HDL cholesterol.)
o Raised fasting glucose
o Central obesity
- More than 35% of Australian adults have metabolic syndrome.
- The frequency of Metabolic Syndrome increases according to gender and age.

Clinical Criteria of Metabolic Syndrome

- Criteria include:
- Waist size
- High triglyceride levels (or drug
treatment)
- Reduced HDL cholesterol (or drug
treatment)
- Elevated blood pressure (or drug
treatment)
- Elevated fasting glucose (or drug
treatment)

Risks Related to Metabolic Syndrome

- Large waist central obesity increased Cardiovascular Disease and Type II Diabetes.
- High triglyceride levels, Reduced HDL, Elevated BP individually associated with
Cardiovascular Disease.
- Elevated fasting glucose, insulin resistance significantly increased risk of Type II
diabetes (although 25% of insulin resistant patients have normal glucose tolerance).

Dangers of Visceral Fat

- Visceral fat is associated with metabolic derangements (insulin resistance, high
triglycerides, inflammation, altered cytokine levels).
- Visceral fat cells secrete less leptin and are associated with high levels of cortisol.
- Metabolically obese (as opposed to being fat or thin).
o May not look fat yet metabolically the visceral fat decreases metabolism.
- Difficult to diagnose with scales.

Difficulties with Diagnosing the Clinical Criteria

- Healthy levels alters depending on age, sex, ethnicity and many other factors making
it difficult to universally diagnose people with Metabolic Syndrome from simple
numbers.

Why Diagnosis is Important

 - Identifies patients at increased risk of CVD, diabetes and chronic kidney disease.
- Increased chances of risks compared to those without the condition.
- Increased risk of mortality and barrier to diagnosis.
Metabolic Syndrome: Social and Political Sickness
Population Health Questions for Metabolic Syndrome
- Problem: chronic condition triggered by weight gain, inactive lifestyle and insulin
resistance. (age and sex etc. are uncontrollable)
- Who has Metabolic Syndrome?
- Where do they live?
- What are the characteristics of the people who develop it? Age, sex, ethnicity, social
status, living location.
- How widespread is it (PREVALENCE) and is it changing/getting worse?
- What stimulates metabolic syndrome.

Metabolic Syndrome as a Function of Inequality

- In countries with greater wealth inequalities there is an
increased proportion of adult obesity.
- As cost of living has increased in many unequal countries,
there has been no equal increase in the real hourly wages
(proportion of wage that is spendable) of the lower percentile
earners to account for the increase in cost of living.
- Resultantly they must turn to cheaper alternatives for
necessities (ie food).
- Occurs in USA.

Role of Epigenetics and Activity Levels in Obesity

- Activity Levels: Major change in activity levels post WWII.
o New evidence that it is the onset of obesity that leads to a decrease in activity
levels, rather than a decrease in activity levels leading to an onset of obesity.
o Many over-weight people still live active life styles (tradies).
- Epigenetics:
o France historically had little available food leading to a decrease in its
populations’ consumption.
o However it is shown from the migration
of Irish and Italians that epigenetics is a
flawed argument.
o Irish upon migration westernised their
diet and gained weight, whereas Italian’s
stuck to their heritage and continued to
consume their local cuisine and remained
relatively healthy.
Metabolic Syndrome as a Result of Changes to Food Production
- Change to food production stimulated by 1970s Richard Nixon re-election campaign.
- Subsidised export of corn for return of palm oil from Malaysia.
- Increase in corn plantations throughout the USA, and decrease in sugar cane lead to
production of fructose corn syrup.
- Fructose corn syrup, very cheap lead to Big Mac cheaper than a Pear.
o FCS is 7x sweeter than cane sugar, and allow cost of Coca Cola and Pepsi to
decrease, lead to decrease in price of production and increase in proportions.
o Protects freezer food from freezer burn.
o Increases life of product.
o Results in 80% super market products containing HFCS55 or sugar.
- Fructose Problems
o When consumed it bypasses chemical breakdown and is stored straight in the
liver (METABOLIC SHUNTING).
o New evidence showing that this promotes insulin resistance.
o Fruit Juice Example
 When fructose dispersed throughout fibre it can be broken down.
 In fruit juice no fibre  increase in fructose consumption that cannot
bebroken down.
 Increase in children receiving ‘fruit nutrition’ as juice.
- Palm Oil
o Imported in USA free trade deal.
o Used to fry McDonalds chips.
o As dense and saturated as beef and pig lard.
o Taste ‘good in mouth’ and stable  does not allow products to
biodegrade in body and increases shelf life.
o Saturated fat  increase BP, cholesterol and body fat.
- Economic Results
o Decrease in food prices and lead to desirable cheap product ready for
consumption.
o Decrease in animal feed prices as animals were fed on mass produced corn.
o Lead to high calories in animals not evolved to eat corn  hypergrowth of
animals.
o Result in high profits from food  monopolies control of food production for
supermarket  factory farming.
o Food production solicited automated, centralised and unregulated labour, gross
mistreatment of human rights.
- Change to Products
o Resulted in an potential for 300 different animals in one hamburger.
o Can lead to increase in contamination and food poisoning (roughly 1900x
more food poisoning cases in USA than AUS).
o Lead to production of supersize products.

Changes to Diet and Shape

 - Industrialisation has had a larger impact on changes to food than the rise of
agriculture.
- Metabolic Syndrome epidemic has resulted due to profound changes in food providers
as we find CHEAPER and EASIER products to consume.

Metabolic Syndrome: Feedings and Weight Control

Peptides Regulating Food Intake
- High levels of redundancy throughout appetite control.
o Means it is difficult to influence a single peptide to
have an effect as multiple peptides for same role.
- Hormones that act in the PNS
o Ghrelin (only peripheral signal to increase appetite.
o Leptin (long term signal due to adiposity)
- Hormones that act in the Brain
o Neuropeptide Y
o Agouti-related peptide
 Both these hormones decrease energy
expenditure.
o Alpha-melanocyte stimulating hormone
 Increases energy expenditure.
- Humans have evolved to deposit a stronger signal to increase appetite to avoid
starvation.

Ghrelin
- Predominantly synthesised in the stomach.
- Increases appetite.
- Found to be inversely proportional to BMI
o BMI = 1/Ghrelin
- Increase in levels at meal initiation and decrease in levels post
meal initiation.
- Binds to receptors GHSR-1a in hypothalamus.
- A decrease in weight brings about an increase in Ghrelin due
to our evolution to avoid malnutrition.

Leptin
- Long term signal, due to secretion from adipose cells.
- Proportional to BMI and fat
o BMI/Fat = Leptin
- Crosses blood-brain barrier via a saturable process or direct
access at median eminence.
- Receptors located in hypothalamus.
- Obesity is defined as a state of leptin resistance.
 - Inhibits food intake via a CNS mechanism.

Hypothalamic Control of Appetite and Body Weight

- Hypothalamus location = either side of 3rd ventricle at base of
brain.
- Two areas important in appetite control.
o Arcuate Nucleus (ARC) at base of hypothalamus.
o Paraventricular Nucleus (PVN)
o Lateral Hypothalamus (LHA)
- Dense cell bodies project from ARC  PVN.
- 2 neuronal population (differentially regulated by leptin).
o Neuropeptide Y (NYP) and Agouti-Related Peptide
(AGRP) are cell bodies that project to PVN and lateral
hypothalamus.
 Inhibited by Leptin.
o Proopiomelanocortin (POMC) cell bodies project to the
PVN and the lateral hypothalamus to release other
peptides.
 Stimulated by Leptin.
o All peptides binds to receptors in the PVN and LHA.

Alpha-Melanocyte Stimulating Hormone (a-MSH)

- Endogenous agonist – 13 AA peptide.
- Released in PVN and LHA.
- Inhibits food intake via MC4R (receptor)
o Tonic inhibition of food intake.
o Alpha-MSH constantly released act as agonist at MC4R.
o MCF4 controls energy dense food intake (fatty foods).
- Levels are regulated by feeding status and leptin.
- Mutation in POMC or MC4R genes result in obesity (4% overall obesity).
- Important for homeostatic adaptations to changes in diet
composition.
- Experiment Graphs
o MCR4 knockout mice had unlimited access to fatty foods
and put on more weight than wild type mice.
o When they were food restricted the wild type and MC4R
knockout mice lost/gained weight at the same rate.

Agouti-Related Peptide (AGRP)

- Within CNS AGRP:
o Synthesis is limited to ARC.
 o Co-localised with NPY
- AGRP competitively inhibits a-MSH at MC4R.
o Has action of increasing food intake via MC4R.
- Level regulated by feeding status and leptin.
- Over-expression results in obesity.

Neuropeptide Y (NPY)
- Member of pancreatic polypeptide family.
o Peptide YY  GIT (anoretic)
- Various actions in CNS and periphery:
o Potently stimulate feeding.
o Chronic administration causes obesity.
- Y1, Y2 and Y5 receptors implicated (Y2 controls release of NPY).
- Reduces energy expenditure.
- Level regulated by feeding status and leptin.

Overview
- Low leptin (decrease in fat mass):
o NPY and AGRP increase
o POMC decrease (decrease a-MSH release)
o Increase in body weight.
- Elevated leptin (increase in fat mass)
o NPY and AGRP decrease.
o POMC increase (increase in a-MSH)
o Decrease in body weight
- Grelin increase NPY and AGRP synthesis and release similar to Leptin.
o No affect on POMC.

Factors Influencing Development of Obesity

- Genetic Factors
o BMI of adopted child strongly correlated to BMI of biological parent.
o 250 geneal and chromosomal regions associated with obesity.
o Obesity has doubled since 1980 so can’t be pure cause.
- Obesogenic Environment
o Decline in physical activity (decrease in exercise rate, increase in technology).
 o Increase in food portion size.
o Increase in sugar-sweetened beverages.
o Increase in energy-dense food (high-fat and sugar content)

Why Do We Overconsume Palatable Foods?

- Control by nucleus accumbens of basal ganglia (drug reward) and ventral tegmental
area of midbrain (sex, water food)
- Bland food not eaten in excess but palatable foods consumed after energy demands
met.
o Well fed rates have access to palatable foods.
o Some individuals pleasure overrides homeostatic signals.
- Contributing factor to obesity epidemic.
- Hedonic value of food influence by metabolic state.
o Hunger increases craving for palatable food.
o Over feeding can reduce activation of palatable food.
- Leptin inhibits activity of VTA dopaminergic neurons.
o VTA neurons express leptin receptor.
o Knocdown leptin receptors on VTA neurons increases food intake and
prefernece for palatable food.
- Ghrelin stimulates activity of VTA dopeminergic neurons
o VTA neurons express ghrelin receptor.
o Increases rewarding value of food.
 Metabolic Syndrome: Type II Diabetes
Pancreatic Beta-Cells as the Sole Source of Body Insulin
- Glucose Homeostasis
o Glucose levels increase rapidly after each meal.
o Insulin levels increase rapidly due to elevated blood glucose
levels.
o Insulin signals to the body that it has entered the fed state.
- Beta-Cell Specificity in Insulin production
- Pancreas is sole source of insulin throughout the body.
- Due to:
o Histone modifications resulting in open chromatin in beta cells.
o Expression of transcription factors related to insulin gene is high in beta
cells to produce the mRNA transcript of insulin.
o Obtain the required cellular machinery in ER for the processing steps in
insulin production.
- This high secretory load of the beta-cells places it at risk of stress events due to high
protein synthesis  ER stress response or unfolded protein causing beta cell death.

Glucose-Stimulated Insulin Release

- Mechanism
1. Glucose entry via insulin-independent glucose
transporter, imitates cascade of events.
2. Increase in ATP from glucose oxidation.
3. ATP triggers close of K+ ATP dependent channels.
4. Results in membrane depol.
5. Ca2+ influx.
6. Stimulates insulin exocytosis.
 - Does not initiate insulin synthesis so relatively fast process.
- Glucagon-like Peptide-1 (GLP-1)
o Hormone that influences insulin release.
o Released from gut cells due to presence of glucose in the
gut.
o Increases cAMP production and amplifies steps regulating
insulin exocytosis.
o Does this without affecting Ca2+ mechanism.

Insulin Initiated Signal Transduction

- Target Cells: Liver cells, Muscle cells and Adipose Tissue.
- Receptor:
o Binding site has high affinity and specific for insulin.
o Has a trans-membrane domain.
o Cytosolic domain initiates the signalling.
o Binding of insulin causes conformational changes to
cytosolic domain.
o Hypothesised to be by either/or:
 Receptor obtains a tyrosine kinase.
 Trans-autophosphorylation.

- Insulin Receptor Signal Transduction

1. Insulin receptor binds to insulin and undergoes
autophosphorylation of its tyrosine residues.
2. The tyrosine phosphorylated insulin receptor
phosphorylates insulin receptor substrate 1 (IRS1) on
specific tyrosine residues.
3. Tyrosine phosphorylated IRS1 acts as a launching site for
multiple signalling changes.
4. In diagram ERK MAPK cascade culminates in changes in
gene expression (transcription).

Insulin Effects in Target Cells

- Insulin effect alters depending on target cell and enzyme
target.

Phosphorylates IRS1 Non-Nuclear Signalling

- After being phosphorylated by the insulin receptor, on its’ tyrosine residue IRS1
affects glucose uptake.
- Mechanism
o IRS1 activates P13K by binding to its SH2
domain.
o PI3K converts PIP2  PIP3.
o PKB bound to PIP3 is phosphorylated by PDK1
and activated.
o PKB phosphorylates GSK3 on its serine residue
inactivating it.
 o GSK3 inactivation does not all Glycogen Synthase inactivation, therefor
synthesis of glycogen is accelerated.
o PKB also stimulates movement of GLUT 4 transporter from internal
membrane to plasma membrane increasing blood glucose uptake.
- This process uses already existing proteins and therefor is relatively rapid.

Insulin Action
- Increase glucose uptake by muscle and adipose tissue.
o Then converted to glucose-6-phosphate.
- Activates glycogen synthase (and inactivates glycogen phosphorylase, glucose 
glycogen).
- Converts glucose  pyruvate via glycolysis and oxidation.
o Pyruvate oxidised to acetyl-CoA where excess acetyl-CoA is used for fatty
acid synthesis.

Pre-Diabetes Diabetes
- Testing
o Fasting blood sugar test
o Glycated haemoglobin (A1C) test
o Oral glucose tolerance test

Insulin Resistance
- Earliest detectable abnormality for type II diabetes.
- Overt type II diabetes occurs when Beta-cells are not able to secrete sufficient
amounts of insulin to offset insulin resistance.
o Insulin Resistance: biological effects of insulin are subnormal for both
glucose disposal in skeletal muscle and suppression of endogenous glucose
production by the liver.
o Blunted/impaired insulin action, due to impaired signalling in
peripheral target tissues.
- Beta-Cell Response in Insulin Resistance
- Blunted, showing lower peak and higher troph in Type II diabetic.
- Molecular Mechanism
o Increase ser/thr phosphorylation on IRS1 protein which inhibits
tyr phosphorylation.
o This results in inactive IRS1.
o Serine phosphorylation can also increase IRS protein
degradation.
o Insulin still binds to receptor, signal transduction is affected.
- Multiple molecular mechanisms work together to produce insulin
resistance.
- An increase in insulin does not always produce normal glucose homeostasis due to
signal transduction problems.

Obesity Effect on Insulin Resistance

- Obesity triggers multiple events that stimulate insulin resistance:
o Ectopic lipid accumulation: cause activation of protein
kinase C.
 o Mitochondrial dysfunction: due to increased levels of reactive oxygen
species.
o Inflammation: increased levels of pro-inflammatory cytokines.
o ER stress: increase protein synthesis/disruption of normal processing creates
an imbalance leading to unfolded protein response  increase serine
phosphorylation  degradation of IRS proteins.
- High fat diet, obesity and inflammation stimulate insulin resistance.

Genetic Disposition in Type II Diabetes

- TCF7L2 Gene is a protein that is involved in Type 2 diabetes mellitus and insulin
resistance.
- Dominant-negative mutants of gene results in cell-cycle arrest in G1 phase.
- Implies growth of Beta-cell mass in early childhood can be determining risk factor for
Type II diabetes.

Metabolic Events and Consequences of Type II Diabetes

- Protein Metabolism
- Absence of insulin:
o No uptake of AAs
o No protein synthesis
o No inhibition of protein breakdown
- Results in muscle wasting (type I characteristic).
- AAs released to liver for gluconeogenesis.
- Contributes further to hyperclycemia.
- Liver Metabolism
- High levels of blood glucose, cells are deprived of glucose as energy supply (no
GLUT4 transporter).
- Liver become net producer of glucose.
- Fatty Acids released during breakdown of triglycerides and ketone bodies in liver
accumulate.
- Ketone bodies released in blood and supply fuel for brain, decrease pH (diabetic
ketoacidosis.
- Changes in diabetics resemble those of prolonged fasting but in absence of LOW
blood glucose.

T2D Phases
- T2D Beta-cell loss is delayed but gradual.
- Fewer B-cells = remaining Beta cells must individually
produce increase insulin.
- Increases stress on remaining Beta cells.
- Beta-cell dysfunction precede and/or accompany Beta-cell
loss.
o Normal response: Ca2+ channels normally localized with insulin secretory
granules  even brief Ca2+ channel opening triggers insulin exocytosis.
o Obesity: exposure to FFA loss of co-localization  Ca2+ continue to open,
resulting increase in Ca2+ intracellularly occurs in wrong place, no secretion.
 - Decline of Beta-cell is multifactorial
o ER stress caused by compensatory Beta cell overproduction lead to Beta cell
necrosis.
 ER stress = imbalance between protein folding capacity of ER and
accumulation of misfolded proteins signalling downstream events
(unfolded protein response).
o Lead to apoptotic and necrotic cell death.

Treatment for Type II Diabetes

- Lifestyle intervention: 150 mins physical activity per week.
- Transcription factors: transcription factors produced at a particular amount call
pathway which produce insulin into account.
- Insulin alternative: antidiabetic agents that affect glucose homeostasis via different
mechanisms.
o T2Ds: increase glucose uptake, decrease lipolysis.
o Biguanides: decrease hepatic glucose production.
o Increase insulin secretion by close K+ channel.
- Gut-Microbiome: sends signals to brain regarding weight control.
- Bariatric Surgery: control weight, altered timing amount of gut hormone secretions
influencing insulin production, increased production of bile acids and surgery
changes.
Future Treatments – Targeting of Insulin Signalling Mechanisms
- Ser/Thr Kinase inhibitors
- Beta-Cell replication
- Stem-cell derived Beta-cells
o Transplanting of stem cells.
o Still need to differentiate into mature beta cells
- miRNAs in regulation of glucose homeostasis.
o miRNAs small non-coding RNA causing translational inhibitor.
o Act as modulators of inflammation-derived insulin resistance, control/tune the
activity of innate immune cells in insulin target tissues.
 Metabolic Syndrome: Prevention and Treatment
Pathophysiology of Metabolic Syndrome: Effect of Visceral Fat
- Triglyceride deposition leads to insulin resistance in muscle.
- Excess visceral fat releases cytokines.
- Increases insulin resistance and promotes lipolysis in fat cells.
- Increase further FFA secretion and further insulin resistance.
- Targets of Visceral Adipose
o Increase in endothelial dysfunction.
o Increase muscle insulin resistance.
o Increase in cardia insulin resistance.
o Increase in Beta-cell apoptosis.
o Increase in Alzheimer’s

IDF Definition of Metabolic Syndrome

- Abdominal (central) Obesity (hallmark) + 2 or more of:
o Elevated TG (1.7 mmol/L)
o Low HDL-C (0.9mmol/L [M]; 1.3mmol/L [F])
o Hypertension (>130/85 mmHg) or treatment for
o Hyperglycaemia (FPG>5.6mmmol/L or IGT or diagnosed type 2 diabetes)
 Improper glucose management.
- Useful way of focusing on subjects at high risk of CVD and
type II diabetes.
- Forms a profound significance for future population health.
- Patterns
 o An increasing number of Met Syn components increases risk of CHD and
Diabetes.

Lipid Abnormalities in Metabolic Syndrome

- Defines as Atherogenic Dyslipidaemia
- Clinically defined as:
o HDL-C < 1.0mmol/L
o Triglycerides > or equal to 1.7 mmol/L
- Characterised by:
o Elevated triglycerides.
o Small LDL particles
o Low HDL-C
- Testing for LDL particles
- Apo B proteins are found in each LDL particle.
- Smaller LDL size correlates with increasing Met
Syn features.
- High Apo B particle numbers = high risk.
- Small LDL particle size = high risk (top)

Insulin Resistance
- Associated with increased risk of coronary heart disease.
- Increase FFA  Increase Glucose (gluconeogenesis) 
Increase in insulin resistance.
- Occurs before overt diabetes.
o Fasting glucose and HbA1c are normal.
o Post prandial glucose is elevated.

Hypertension
- Increase in 20 mmHg systolic and 10mmHg diastolic doubles CVD disease risk.
- Antihypertensive drugs decrease incidence of fatal cardiovascular events.

Treatment Strategies
- Address glucose intolerance (preventing diabetes)
- Reduce cardiovascular risk
o Address dyslipidaemia
o Treat hypertension

Lifestyle Treatments: Weight Loss and Exercise

- Walking faster may reduce diabetes risk.
- Those who decrease their food intake and increase their
exercise are 57% less likely to develop diabetes.
- Obesity Management
- Place on Very Low Calorie Diet (VLCD).
 o VLCD entails:
o 800kcal/day
o Greater or equal to 50g of high-quality protein and AA.
o Provide essential FFA.
o Provide daily trace elements and vitamin requirement.
o Induce ketosis to supress appetite.
o Recommended for BMI > 30.
o Intensive phase (2-3 meal replacements) 8-16 weeks.
o 2 cups of salad and low-starch vegetables eaten to provide fibre to lessen
hunger/constipation.
o Tablespoon of oil/butter to prevent gallstones.
- Rapid weight loss proven to be more effective than gradual.
- Laparoscopic Band Surgery
o Very Effective in preventing diabetes.
o Due to decrease in weight.

Pharmacological Treatments: Liraglutide

- Liraglutide = GLP-1 receptor agonist.
o Acts to induce insulin secretion.
- Only found to be active when insulin levels are
normal, not low  doesn’t induce hypoglycaemia.
- Acts to increase active time of GLP-1.
- Administration of these drugs show a:
o Increase in weight loss
o Decrease in Met Syn

Pharmacological Treatments: Metformin

- First treatment in Type II diabetes.
- Inhibits hepatic glucose production.
- No weight gain; no major hypoglycaemia.
- GI intolerance in main SE, (minimised by slow release form.
- 40% reduction in diabetes.

Cardiovascular Risk in Metabolic Syndrome Patients

- Relative Risk: individual’s risk of cardiovascular disease relative to the general
population.
- Absolute Risk: actual risk of cardiovascular event occurring in a given time period of
an individual.
o Defined as risk of an event in next 5 to 10 years.
- An increase in Met Syn risk factors increases risk of CVD.
- Statin Therapy
o Reduced CVD risk 30-40%.
o Risk reduction is similar in people with high or normal LDL levels.
o Treatment guidelines are based off absolute risk rather than LDL levels.
 Metabolic Syndrome: Gut Microbe
Constituents of the Gut Microbe
- Self-sustaining ecosystem.
- 90% of gut microbe made up of:
o Firmicutes
o Bacteroidetes
o Actinobacteria
o Proteobacteria
- Diet has dominant role in shaping gut microbiota.
- Microbiota consume dietary fibre.

Gut Microbiome by Ecology

- Probiotics: transient commensals: confer health benefits and affect beneficial
bacteria.
- Autobiants: permanent symbiotic, immunomodulatory. Part of normal microbiota,
direct influence on host metabolism and immune function.
 - Pathobionts: permanent, parasitic/infectious; do not cause disease in presence of
normal microbiota. Cause disease when microbiota/immunity perturbed.
- Autobiants
o Express polysaccharide utilization loci (PUL) and enzymes involved in
digestion of complex carbohydrates.
o Bacteria with specific PULs can be selected by local diet.
o Results in ability to identify microbiota based on diet.

Short Chain Fatty Acids

- Bacterial fermentation results in production of
SCFA.
- Functions (gut maintenance and immunity)
o Competition exclusion (crate anaerobic
environment)
o Stimulation of mucous production.
o IgA production
o Tissue repair.
o Promotion of Treg cells, tolerance.
o Inflammasome activation IL-18 production
and epithelial integrity.
o Suppression of Th17 cells and
inflammation.
- Regulates G-protein coupled receptors.
- Acylated histones and transcription factors.

Diet Influences on Gut Microbe

- Low fibre diet leads to:
o Loss of gut integrity
o Increased sensitivity to enteric pathogens.
- Due to breakdown of mucus layer that lines
epithelium.

Causal Role for Gut Microbiota in Human Health and Disease

- Led to identification of individual bacterial
species/metabolites associated with particular
disease.
- Conversion of cholesterol  coprostanol in gut
reduces cholesterol uptake.
o Increase in cholesterol = increase CVD
risk.
- Identified by correlating gene expression with coprostanol levels.
- Bacterial species are sensitive to inflammation in Crohn’s Disease, leading to
increased risk of CVD.
 - Limitations: most correlations are not causal, limited knowledge of majority of
microbiota genes or chemical characterization of
metabolites.
- Starting with Mechanism
o Bioactive molecules have an effect in vivo.
o Allows more targeted analysis of correlation.
o Use metabolomics and genome sequencing
to identify ‘active’ metabolite and putative metabolic pathway.
o Microbial metabolites activate human dopamine and histamine receptors.

Link Between Gut Microbiota and Obesity/T2D

- Correlative Links Include:
o Risk of T2D linked to High GI diets and negatively correlated with dietary
fibre intake.
o Low gut diversity (gene count) associated with weight gain, obesity, insulin
resistance, fatty live and low-grade inflammation.
o Administration of soluble fibre (inulin, resistant starch), to human subjects can
reverse many of abode.
o Early antibiotic use linked to weight gain later in life, increase in bacterial
special associated with T2D.
- How Does Gut Microbiota Contribute to Obesity, Met Syn and T2D
o Altered calorific intake.
o Direct modulation of glucose and lipid metabolism.
o Alteration in mucosal/gut barrier functions.
o Direct/indirect modulation of immunity and control of inflammation in
multiple tissues.
- Low fibre diet  reduced SCFA production, depletion of gut mucosal layer, reduced
barrier function and endotoxemia Mucosal Associated Invariant T-cells recognise
microbiota produced Vit B1.

Metabolic Syndrome: Cardiovascular Risk Factors

Risk Factors
- Established Risk Factors: When reversed the incidence of subsequent coronary
disease is reduced.
o High LDL and VLDL cholesterol.
o High BP
o High BMI
o Smoking
 o Diabetes
- Non-Established risk factors
o Left ventricular size
o Fibrinogen (clotting factors)
- Increase in BMI increases all risk factors.
- Risk factors tend to aggregate.

Common Risk Factors

- CHD commons risk factors include:
- Age
o Single most important risk factor.
o 80% > 65 years.
- Sex
o Greater in males.
o Men die earlier.
o Females increase chance after menopause.
o Hormone therapy does not reduce CHD.
- Lipids
o High LDL and VLDL levels associated with CHD.
o Triacylglycerol variable so difficult to measure, therefor difficult to associate
with.
- Weight
o Especially central adiposity.
- BP
- Risk rates for CHD are usually expressed after adjustments for age and sex.

Popular Risk Factors

- Family History
o CHD in a first degree relative increases risk 4-fold.
o Genes and environment.
- Stress = unproven.
- Alcohol
o Two units per day associated with decreased chance of CHD.
o Increasing after that increases chance.

Patients and Populations

- Increase in 10mmHg systolic BP,
doubles risk of coronary disease.
- Assessing CVD Risk
 o Most people die with average risk, as largest proportion of people have
average risk.
o Risk * Pop No = Total Deaths
- Medical Models are targeted at high risk section.
- Population models are targeted at average risk section.

Epidemic of CHD
- CVD deaths largest cause of death in the world.
- Rising in developing countries (fast food).
- Fallen in developed countries.
- Important Population Factors
o Nutrition
o Cigarette smoking
o Others
- Japan
o High smoking rates
o Low consumers of medical care
o Low fat diet
o Average age 86, UK 81

Metabolic Syndrome: Clinical Consequences

Synergistic Damage of MetS
 - Unholy trinity:
o Hypertension
o Dyslipidaemia
o Hyperglycaemia
- Increase adiposity.
- All exacerbate each other.

Dyslipidaemia
- Dyslipidaemia  Increase Adiposity
- Hallmarks
o High LDL:HDL ratio
o High total cholesterol level
o High triglyceride leve
- Mechanism
- Cholesterol, FFA and Triglycerides travelling in blood = worst
compartment.
o Results in increase of atherosclerosis, carried in foamy
macrophages.
- LDL, VLDL, IDL aid in mobilising cholesterol from liver 
blood  adipose tissue, muscle and steroid rich organs.
- LDL takes cholesterols  foamy macrophages, accumulate in atheromatous plaques.
- HDL takes cholesterol blood  liver storage.
- HDL takes cholesterol out of foam cells.
- More dietary triglycerides are broken in FFA, more adipose tissue.

Atherosclerosis
- Dyslipidaemia + Increased Adiposity  Hypertension
- Hallmarks
o Fatty streaks in tunica intima (harmless)
o Progress to atheromatous plaques.
- Mechanism of Plaque
- The plaque builds up.
- Over time development of scar tissue (fibrous cap).
- Decreases lumen size (increasing MAP)
- Clinical Consequences
o Lead Time: reversible injury.
o Clinical Horizon: symptomatic presentation of
underlying silent disease.
o Irreversible hypertension due to decrease of
arteriole diametes.

Insulin Resistance
- Hyperglycaemia  Increased Adiposity
 - Hallmarks
o High levels of fasting blood glucose.
- Mechanism
- Increase in adipose tissue  increase glucose uptake and lipogenesis and decrease in
lipolysis.
- Striated muscle  increase glucose uptake, glycogen and protein synthesis.
- Liver  decrese gluconeogenesis, increase glycogen synthesis and increase
lipogenesis.
- Development of hyperinsulinemia.
- Clinical Consequences
o Decreased fertility.
o Development of T2DM.

Persistent Hyperglycaemia - T2DM

- Hyperglycaemia  Hypertension
- Synergistic damage between hypertension and hyperglycaemia created by pro-
inflammatory state mediated by Advanced glycation end products (AGEs).
- Increase likelihood of cancer  increased cell proliferation/decreased apoptosis 
Neoplasia  Invasive Cancer
- AGEs
o Stimulates smooth muscle proliferation at arterioles  hyaline
arteriolosclerosis.
o Organs rich in arterioles will sustain more hypertensive damage (retina, brain,
kidneys). With T2DM.
- Persistent Mechanism: Infection
o Increase risk of infection due to glycation of components of immune system
that makes their response less effective.
o Bacteria thrive in high glucose environment.

Fatty Liver Disease (FLD)

- Mechanism
o Increased fat deposition  inflammation
(steatohepatitis)
o Gradual replacements of functional hepatocytes.
o Common cause for a liver transplantation.
o Prolonged inflammatory state  risk for cancer.

Clinical Consequences of MetS

- Clinical Consequences (sequelae)
o Vascular problems.
o Locomotor problems.
o Brain and nerve problems.
o Immunity and infection problems
o Fertility and Maternal-Fetal problems.
o Oral and dental problems
o Cancer risk
Hypertension
- Definition: persistently elevated systemic blood pressure > 140/90 mmHg.
o Or already taking anti-hypertensive medication.
- Clinical Consequences
- Primary HTN vs Secondary HTN
o Primary = no single obvious cause found.
(majority), multifactorial.
o Secondary = HTN due to isolated identifiable causes
(endogenous (internal) exogenous (external))
- Chronic HTN vs Hypertensive Crisis
o Chronic = 140-180/80-120 without acceleration in
increase in BP.
 Minimise risk/lifestyle factors.
o Crisis= immediate action, gradually lower BP
slowly over 24-48 hours.
- End Organ Damage
o Causes gradual progressive damage in multiple organs.
o Key organs: vessels, heart, kidneys, brain, eyes.
o Factors determining degree of end-organ damage:
 Severity of systemic HTN.
 Extent of transmission of systemic HTN to the kidney.
 Tissue susceptibility to barotrauma.
- Complications
o Vascular damage, Heart damage, Kidney, Eyes, Brain, Sexual Dysfunction.
- Patient Review
o Confirm BP and triage for immediate problems.
o If chronic and stable HTN: identify and address risk factors and causes.
o Assess existing end-organ damage.
o What to monitor.
o Check goals and adherence to medication and management plans.
o Decide if Primary vs Secondary
- Risk Charts top right = most at risk.

Prevention of MetS
- Primary: trying to prevent onset of getting disease.
- Secondary: detect a disease early and prevent it from getting worse.
- Tertiary: Improve quality of life and reduce symptoms in a disease one already has.
 Metabolic Syndrome: Wrap Up
Roles of Plasma Lipoproteins in Lipid Transport
- Cholesterol
o Precursor to steroid hormones, bile salts and Vit-D
o Not made in plans
o Need for cell membranes
o Humans can produce necessary cholesterol.
- Transport of Cholesterol
- Occurs via 2 pathways:
o Fatty acid esterification on 3-OH group (makes fully hydrophobic)
o Incorporate into protein/lipid composites (lipoproteins such as VLDL for
delivery to tissues).
- Allows cholesterol to be delivered to right locations

Lipoprotein Transport
- Exogenous Pathway
- Chylomicrons carry dietary lipids to tissues.
- Remnants are taken up by the liver degraded in lysosomes.
- Endogenous Pathway
- Diet has excessive Fatty Acids (FAs) and Cholesterol (C) (carbs  triaglycerols,
TAGs)
- FFA  TAGs and C to Cholesterol Esters (CE) and packaged in VLDL transported to
muscle and adipose.
o When insulin high – VLDL moves
dietary lipids to adipose (storage).
o When insulin low – VLDL moves
dietary lipids from adipose to muscle
(oxidation for energy).
- Removal of TAGs from VLDL produces LDL
(rich in C/CE).
- LDL carries C to tissue (muscle, adipose,
adrenal) and macrophages (foam cells).
- Excess LDL returns to liver – C (membranes
bile acids stored as CE in lipid droplets.
- Reverse Cholesterol Transport
- HDL originates in the liver and small intestine.
- HDL Picks up C from macrophages and foam
cells.
- HDL returns C to liver which is transferred to
LDL.
- Enterohepatic Pathway
- C is a precursor for bile salts which can be reabsorbed and returned to gall bladder.
Mechanism After Ingestion
1. Bile salts emulsify dietary fats in small intestine  mixed
micelles.
2. Intestinal lipases degrade TGAs.
3. FAs and other break down products taken up by intestinal mucosa
 TGAs.
4. TGAs incorporated with C and apolipoproteins into chylomicrons.
5. Chylomicrons move through lymphatic system and bloodstream
into tissues.
6. Lipoprotein lipase, activated by ApoC-II in capillary converts
TGA  FA and glycerol.
7. FAs oxidised for fuel or re-esterified for storage.

Atherosclerosis: Dyslipidaemia
- Monocytes  Macrophages and engulf modified LDL  Foam
Cell
- Mechanism
o Monocyte attracted to oxidised lipoproteins that aggregate and stick to ECM.
o Monocyte differentiates  macrophage
o Macrophage ingests lipoprotein  Foam Cell
o Modified LDL accumulates in an artery wall (favoured by high LDL)
o Endothelial cells display adhesion molecules.
o White cells (monocytes and T-cells) invade tissue and secrete inflammatory
mediators (cytokines).
o Macrophages take up LDL using scavenger
receptors.
o Macrophages become engorged with
cholesterol (foam cells).
o Fibrous tissue (plaque) develops to trap the
foam cells  atheroma.
o Foam cells produce “tissue factor” that can
lead to blood clot in artery upon rupture of
plaque.
- Reverse Cholesterol Transport
o HDL picks up cholesterol from non-liver tissues
(foam cells) at growing plaques.
o HDL carries cholesterol back to the liver.

Cholesterol Synthesis
- How to reduce serum cholesterol
 o HMG-CoA reductase = rate-limiting enzyme in cholesterol synthesis.
o Statins are competitive inhibitors of HMG-CoA reductase (decrease
cholesterol levels).
- Mechanism
o Acetyl-CoA is generated in mitochondria.
o Acetyl-CoA  HMG CoA.
o HMG CoA  cholesterol.
o Cholesterol negatively inhibits HMG CoA reductase.

Sucrose, Glucose and HFCS

- Sucrose is similar in composition to HFCS.
- Glucose and fructose metabolism are interconnected,
overlapping and different.
- Fructose Metabolism
o Fructose-1-Phosphate is cleaved to give DHAP and
Glyceraldehyde, not GA-3-P
o Fructose is preferentially sent to liver and
converted to glycerol.

Short Chain Fatty Acids

- Major end-products of anaerobic fermentation of fibre.
- Directly modulate gut microenvironment, function and host immunity.
- Directly modulate signalling pathways in different tissues and immune cells.
- Promote anti-inflammatory immune response.
- Progress of Inflammatory State
o Lean: TAG diet = TAG catabolized.
o Overweight: TAG diet > TAG catabolized.
o Pro-inflammatory states: Enlarged adipocytes produce macrophage
chemotaxis protein (MCP-1)
o Chronic inflammation: macrophages
infiltrate adipose tissue in response to
MCP-1.
o Macrophages produce TNFalpha which
favours export of FAs.
o Adipocytes export FAs to muscle where
ectopic lipid deposits form.
o Ectopic liquid interferes with GLUT4
movements to the myocyte surface,
producing insulin resistance.
- AMPK enzyme burns fuels during exercise and starvation, treatment for type II
diabetes.
 Introduction to Stem Cells
Formation of Cell Types
- Embryogenesis: Cells become restricted in developmental capacity.
- All cells = same genes, certain genes are actively transcribed.
- Gene regulations occur:
o Promoter sequence regulatory elements.
o Changing of chromatin structure (DNA epigenetics).
o Heritable changes.
- Waddington Epigenetic Restriction
o Undifferentiated cells of embryo = top of hill
o Differentiation seen as gradual restriction of fate.
o Tissue formed = substantial cell division and differentiation to
ensure tissue integrity.

Stem Cell: Definition

- Definition: A cell that has the ability to divide (self-replicate) for indefinite periods
and can give rise to many of the differentiated cell types that make up an organism.
o Self-Renewal must be possible.
- Classification of Stem Cells
o Totipotent: can give rise to a new individual given
maternal support. (Zygote)
o Pluripotent: can give rise to all types of adult tissue
cells. (iPSC, embryonic SC)
o Multipotent: can give rise to several types of mature
cell. (Haemopotic SC, Tissue SC, Sdult Stem Cell)
- Can also be classified on their location  tissue SC, adult
SC, adult tissue SC.
- Multipotent SC  create tissue from their tissue of origin.
o Blood SC  RBD, Platelets, WBC.
- View stem cells as a hierarchy of potential.
- Cell turnover suggests presence of adult tissue stem cells.
 - Mechanism
o Stem cells in tissues divide rarely but give rise to transit amplifying cells.
o Can give rise to differentiated progeny and other stem cells (self-renewal).
o Give rise to other cells after transplantation.
o Descendants of stem cells are functional.
- Stem Cell Characteristics 
o Self-renewal/differentiation.
o Give rise to transit amplifying cell compartment
committed cells with limited division capacity.
o Often lacking in specialised organelles (high
nucleus: cytoplasm)
o Long lived-express telomerase.
o May be restricted spatially to specific zones or
niches.

Adult Stem Cells in Tissue Repair

- One hematopoietic stem cell (HSC) can
repopulate entire hematopoietic system.
- Proven by transplantation after bone marrow
ablation.
- Basis for ‘bone marrow’ transplantation for
the treatment of leukemia.
- Allows for bone marrow transplants during
chemotherapy.

Intestine Crypt Stem Cells

- Small number of rapidly diving stem cells in crypt at base of villi.
- Regulated by Paneth cells that regulate their turnover.
- Form  transit-amplifying cells = intermediate cells whose tole is to increase
cell no rapidly.
- TA cells can form either  epithelium,
goblet cells or enteroendocrine cells.
- Eventually lost from top of villus.
- Lineage analysis proves  one stem cell
generates whole villus.

Application of Adult SC
- Extrinsic signalling from surrounding cells, regulates SCs.
- Turnover of Adult SC assist in improving repair.
- Mobilisation of SC can allow for their harvest and
transplantation.
- Isolating adult SC model disease and screen for treatments.
- Modelling Disease using Epithelial Stem Cell Organoids
o Use derived gut organoids to screen personalised
response to drugs.
 o Organisation and response to demands of growth or repair require there be
restrictions on developmental potential of adult SCs.
o Limits are imposed by molecular restraints, on gene expression and are
heritable during many rounds of cell division.
o An adult SC may show relaxation of these restrictions in an altered
environment, possibly accounting for plasticity. Even so, plasticity is observed
at low freq.

Pluripotent Stem Cells

- Grown indefinitely in vitro.
- Maintain normal genetic makeup.
- Capable of differentiation  wide range of somatic tissues in vivo and in vitro at high
freq and under range of conditions.
- Capable of colonising all tissues (inc germ line) after blastocyst injection to give
chimeric offspring.
- Not able to recreate an entire organism, not capable of generating extraembryonic
tissues.
- Source induced Pluripotent Stem Cells (iPS) Mechanism
o Isolate cells from patient (skin or fibroblasts).
o Treat cells with reprogramming factor, wait few weeks.
o Pluripotent SC forms, change culture conditions to induce differentiation into
a variety of cell types.
- Return to Pluripotent State
o Retroviral or lentiviral transduction.
o Adenoviral transduction.
o Plasmid transfection.
o Protein transduction.
- iPS Properties
o Form any cell of human bodies.
o Human insulin producing cell clusters generated from human iPSC (replace
beta cells in insulin resistance).
o iPSC can form mini-kidney organoids in a dish.

Applications of Stem Cells

- Simultaneous gene correction and reprogramming of patient fibroblasts to iPSC.
- Generation of kidney organoids from patient derived iPSC.
- iPSC used in heart defects and heart disease.
- Neurodevelopmental Disease
o Modelling the disease to understand case.
o Discovering novel drugs to mitigate or even prevent the disease behavioural
outcomes.
o Precision medicine to treat individual underlying causes and symptoms.
- Inherited Kidney Disease and Kidney Failure
o Rebuilding transplantable kidney tissue from stem cells.
o Using 3D cellular bioprinting to make kidney tissue from stem cells.
o Successful transplantation into animals.
o Transplanted tissue matures and shows blood flow.

Innovations
 - New tools to study human biology in health and disease.
- New understanding of tissue repair
- Stem cell-derived human tissues to improve diagnosis, study disease mechanisms and
screen for new treatments.
- Cells for replacement therapy in devastating conditions involving cell loss or injury.

Stem Cells: Cellular Therapy for Endogenous

Repair
Tissue Homeostasis and Endogenous Repair
- Properties
o Cells regenerating to stay the same.
o Cells and tissues continually ‘turn over’ depending on organ system.
o Different tissues and organs have different capacities for regeneration.
o Homeostasis relies  specific cells maturing into functional progeny and
recapitulating the structure and function of progeny.
- Repair
o Depending on type of disease or trauma tissues have different patterns of
response.
o Regeneration of functional cells and cell organisation within tissue.
o Fibrosis stimulated by inflammatory cell response to disease/trauma/cell
death.
- Endogenous Repair
o Relies upon intrinsic ability of cells to proliferate and differentiate into mature
functional progeny.
o Signals for proliferation and differentiation may depend on cues from cellular
microenvironment.
o LGR5+ cells in intestinal crypts.
o Haemopoietic Stem Cells for immune system.
 - Microenvironment determines signalling of SC proliferation.

Stem Cells as Cellular Therapy

- Every Medical Intervention relies on manipulating pre-existing biology.
- Use of SC as cellular therapy:
o Ability to transfer tissue from one site/person  another.
o Overcoming immunological barriers if cell/tissue transferred between non-
identical people.
o Intrinsic ability of cells for tissue for regeneration.

Haemopoietic Stem Cells

- Properties
- Cells with ability to regenerate all functional cells of blood system (pluripotent).
- Ability of self-renewal.
- Possess unique properties: rare, quiescent (not in active cell cycle), resistant to
cytotoxic stress and radiation therapy, identifiable by specific genes of surface protein
combinations.
- Stem Cells as Cellular Therapy
o Transfer tissue one person to another.
o Overcome immunological HLA barriers if transferred between non-identical
people.
 HLA matching
 Immunosuppression
o Intrinsic ability of cells to regenerate haemopoietic system.
o Potential use of innate immune system of non-identical donor as an
immunotherapy.
o Amenable to genetic manipulation.

Haemopoietic Stem Cells as Cellular Therapy

- Tissue Transfer from one person to another
- Bone marrow harvest
- G-SCF mobilised peripheral stem cells
o Mobilises SC in blood.
- Umbilical Cord blood stem cells

Bone Marrow Transplantation for Blood Disorders

- Replace or Repair (iatrogenically) damaged or diseased Haemopoietic system.
o Blood disorders, bone marrow failure syndromes and immunodeficiencies.
- Allow use of (legal) high-dose chemotherapy or radiation therapy against disease.
o Blood cancers, solid cancers.
- Potential use of innate immune system of non-identical donor as an immunotherapy.
o Blood cancers.
- Amenable to genetic manipulation.
o Modification of SC to “correct” disease haemopoietic system.
- Mechanism
- Autologous Stem Cell Transplant Therapy
 o Repair/Reconstitution of Blood Cell System after treatment resulting in
otherwise lethal bone marrow failure.
- Allogenic Stem Cell Transplant Therapy
o Repair/reconstitution of Blood Cell System after treatment.
o Healthy Donor without Blood Disease
o Immunotherapy for Graft vs “Disease”

Risk/Complication of Haemopoietic Transplantation

- Transplant Conditioning
- Chemotherapy/Radiotherapy (Total Body Irradiation)
- Transplant Specific Complications.
- Graft vs Host Disease
o Occurs potentially in Allogenic Transplant.
o Requires immunosuppression to decrease host immune system rejecting
transplantation.

Gene Editing for Correction of Genetic Diseases

- Beta-globin haemoblobinopathies: Single
Gene defects.
- Sick Cell Anaemia
o Severe Sick Cell Patients HbS/S = life-
long red cell exchange.

Stem Cells: MSC and Respiratory SCs

Mesenchymal Stem Cells
- Bone Marrow MSCs
- Multi-lineage differentiation.
- Adhere to plastic.
- Fibroblastic morphology.
- Can form colonies (CFU-F) when piated at low density.
- Colonies can be quantitated for MSC incidence and size.
- Incidence of BM MSCs
o 1-3 MSC per 100,000 MNC (very rare).
o In vivo/vitro studies show link BM MSCs 
perivascular cells.
o Pericytes are important in regulation of HSCs in the
bone marrow niche.
- Beyond Bone Marrow
o Come from many different areas.
 o Proliferate to many different cell types.
- Potential = Multipotent.

MSC Mess
- Variability and Ambiguity in:
o Tissue of derivation.
o Method of isolation.
o Rigour of evaluation (compared to HSC)
o Definition is based on use of in vitro model
- lack of in vivo models.
- Nomenclature = single name used.
- Implies all cells are the same regardless of origin.
- MSC from widely different tissues often
considered equivalent in clinical applications.
- Leads to inaccurate nomenclature.

MSC Immuno-Modulation
- Cell therapy  Cell mediated therapy.
- Mechanism
o MSCs secrete paracrine factors.
o Decrease immune response.
o Decrease inflammation.
- Graft vs Host Disease
o Complication of allogeneic bone marrow transplantation.
o Activated donor T-cells attack recipient tissues.
o Occurs in 35-50% of hematopoietic SC transplant.
o Treatment: steroid administration, immune-suppressants, monoclonal
antibodies TK inhibitors.

Cells in the Lung

- Large repertoire of cell types with specific roles.
- Distribution of respiratory epithelial cells alter from proximal to distal regions.
o Stem cells reproduce cells for the
specific region.
- Development of the Lung
o Epithelial cells develop in one
direction.
o Mesenchymal cells develop in the
other direction.
o Paracrine and Autocrine factors
determine the production of epithelial
or mesenchymal cells.
- Mesenchymal Lung Populations
- Lgr6+ comprises smooth muscle cells surrounding airway epithelia.
 o Promote airway differentiation of epithelial progenitors  Wnt-Fgf10 co-
operation.
- Lgr5+ located in alveolar compartments.
o Sufficient to promote alveolar differentiation of epithelial progenitors through
Wnt Activation.
- Proximal SC develop into proximal cells of lung.
- Distal SC develop into distal cells of lung.

SC Therapy for Respiratory Diseases

- Asthma, COPD, Interstitial Lung Disease
- Diverse pathophysiology.
- Interact with ECM, inflammation, epithelium and mesenchyme.
- Challenges
o Diversity of cells.
o Complex topology of lung.
o Manipulation of microenvironment.
o Range of disease pathophysiology.
o Paucity of cell surface markets to isolate and enrich progenitor cells.
- Approaches
- Clinical applications:
o Regenerative Medicine: cellular therapy, regulation of endogenous SCs.
o Bioengineering: Decellularization.
 Series of mechanical, enzymatic and/or chemical treatments (removal
of cells of organ).
 Provides, acellular, naturally occurring 3D scaffold.
 Ultra-structure and arrangement of native and complex ECM are
preserved.
 ECM is highly conserved across species, well tolerated across
individuals.
 Mechanical properties of tissue are retained.
o Gene Therapy: Cystic fibrosis.
o Immunomodulation: Mesenchymal stromal cells.
 Injected or implanted MSC, re-establishes micro-environment.
- Prochymal: allogenic MSC, bone marrow, acquired by mesoblast.
- Cymerus: iPS cells  MCA precursor  MSC.

Summary of Difficulties
- Lung is complex and highly regulated organ.
- Complex architecture and array of cell types.
- Repair recapitulates ontogeny.
- Epithelial   Mesenchyme communication is essential and reciprocal.
- Regional specific populations of progenitor cells in the adult lung.
- Diverse pathophysiology of respiratory diseases requires customised approach for
biological therapies.
o Repair or restore the lung microenvironment.
o Cellular reonstitution.
 Stem Cells: Organoids and Intro to Tissue
Engineering
Organoids
- Definition: collection of organ-specific cell types that develops form stem
cells or organ progenitors and self-organizes through cell sorting and
spatially restricted lineage commitment in a manner similar to in vivo.
- Description
 o 3D tissue cultures.
o Derived from stem-cells.
o Proliferate and Self-Assemble.
o Recapitulate some function of organ derived from.
o Resemble ‘mini organ’
- Source
o Can be derived from epithelial stem cells.
o Also derived from Inner Cell Mass of
Blastocysts (ESC) and somatic cells (iPSC)
pluripotent stem cells.
- Formation
o Intestinal organoids where first to be used and formed.
o Crypt domain obtains Lgr5 SC with Paneth cell, similar to crypt of intestine.
o Lgr5 SC isolated from intestine  grew in matra gel  pro/differentiates in
organoid.

Drug Discovery and Disease Modelling

- Stem cell  Organoid development is new.
- Advantages of Organoids in Drug Discovery
o Provides semi physiological environment.
o High throughput screening.
o Biobanking.
o Genomic editing.
o Can assist in model human development and disease.
o More similar to animal models than 2D Cell Cultures
- Method of Drug Research with Organoids
o Diagnostic/Prognostic use
o Personalized drug response testing (pre-test for effectiveness and dangers)
o Targeted genetic correction.
- Cystic Fibrosis
o Many different mutations.
o Replicate Cystic fibrosis mutations in an organoid.
o Forskolin induced swelling of organoid to help
identify mutation of CF.
o Can develop organoids to identify which drugs are
effective against CF for that patient (identify which
mutation is present).

Application of Tissue Engineering

- Transplantation
- Normally require human donor (low levels of organ donors).
- Organ rejection - require immune-suppressants.
- Transplant rejection  damage other functional and healthy tissues.
- Prostheses
- Requires replacement.
- Provides structural support but often limited function.
 - Tissue engineering  overcomes these issues.

Mechanism of Tissue Engineering

- Process of growing new tissue/organs for maintenance/repair/improvement/
replacement of damaged, diseased, or poorly functioning tissues or organs.
- Biological approach to regenerative medicine (regrow tissues + organs).
- Limitations
- Complexity of Tissues = increasing
engineering complexity.
o Increasing functional parameters
o Increasing metabolic requirements
o Increasing cellular interactions
o Increasing inter-organ interactions
- Vasculature
o Any tissue >400um must be vascularised (O2 diffusion limited to 150-200)
o Provide biochemical signals within transplant to promote  angiogenesis +
vascularisation (VEGF/PDGF/FGF).
o Vascularisation most successful when pre-implanted (endogenous
angiogenesis/vascularisation).

Design Considerations of Tissue Engineering

- Cells
o Autologous (own body) vs Allogenic (same species).
o Differentiated (mature) vs Undifferentiated (SC or Progenitor)
o Decision making process as to how to obtain the cells.
- Extracellular Matrix
o ECM comprised of a complex and dynamic network of
macromolecules.
o Proteins and polysaccharides assemble into organised
meshwork.
o Distribution and composition of ECM in different tissues
unique.
o Provides structural support, regulating cell-cell communication,
sequestering
of growth factors, and signalling molecules.
o Equal cells behave differently depending on microenvironment to which they
are introduced (ECM).
- Scaffolds
- 3D biomaterials:
o Direct organisation, growth and differentiation of cells in the process of
forming functional tissue.
o Maintains space and provides structural support (biological and mechanical
cues).

- Characteristics
o Biocompatible (acceptable to body)
o Tissue appropriate (mimic native ECM)
 o Support transplanted or endogenous cells (attach, survive, proliferate and
differentiate)
o Biodegradable (transient structure - gradual degradation/remodelling, promote
native ECM production)
o Naturally occurring (polypeptides and polysaccharides, recognised by cells)
o Synthetic (modify degradation rate, reproducibly manufactured with
mechanical properties.)
- Different Properties achieved by
o Porosity (permeability)
o Cell adhesion and biorecognition
o Water content
o Mechanical properties
o Resorption and degradation.
- Signalling Molecules
- Engineered tissue influenced by soluble growth factors.
o In vitro - soluble factors can drive differentiation of cell types.
o Commonly  BMPs, FGF-2, VEGF, and TGFBeta1.
o Chiefly soluble factors incorporated  ECM during scaffold fabrication.
- Decellularization
o Series of mechanical, enzymatic and/or chemical treatments to remove cells
from organs.
o Provides acellular, naturally occurring 3D scaffold.
o Ultra-structure and arrangement of native and complex ECM are preserved.
o ECM is highly conserved across species.
o Mechanical properties of tissue are retained.
- 3D Printing
o Precise control of architecture.
o Control, density, functionality, shape to mimic organs.
o Controlled gradients in mechanical properties.
o Controlled gradients of biologically active factors.

Tissue Engineered Protein

- Reason for engineering protein:
o Environmental sustainability (pollution and resources required to look after
animals.)
o Ethical reason (animal welfare)
o Health and Safety (lower risk of animal disease).
- Mechanism
o Create myotubes and muscle fibres from ESC or iPSC.
- First invitro burger made from 20,000 muscle strips.
 Stem Cells: Regenerative Medicine and Ethics
Ethical Considerations: Derivation and Use of Cell Lines
and Steps to Develop New Stem-Cell Medicines
- Rigorous evaluation is essential.
- 4 phase system to assess safety and effectiveness.
- Becoming more accessible to public.
o Cheaper
o Safer
- Application of SCT
- Cell Therapy = Mesenchymal Stem Cells
- Propose Method of Action
o Encourage body to repair itself
o Reduce inflammation
o Prevent Further Damage

Community Expectations: Ethical Decisions

- SCT therapy remains unproven.
- Presented as a universal truth without clinical trials.
- Commercialisation of STC has become a profitable business.
- Interfered with Clinical Research as lack of restrictions on commercial industry
makes business stem cell therapy makes it more appealing.
- Steps to Combat and Disrupt Business Model
o Challenging commercial world.
o Call for evidence.
o Recent calls for a regulatory reform of the industry.
 Enforce professional standards
 Address regulatory ambiguity
- Australia Issues
o Lack of options in Aus.
o Support from health professionals is low due to lack of evidence.
o Many travel abroad for treatments.

Regulations Address Concerns

- Prohibited for SCT
o Creation of embryo for research purposes.
o Creation of hybrid embryo
o Creation of embryo with genetic material of more than two persons.
o Use of an ART embryo that is not excess
o Use of embryo without a licence.
o Payment for donation of embryos or eggs.
o Transfer of an embryo generated by SCNT to the uterus of a women or
animal.
- iPS is the ethical alternative.
- Presents new ethical challenges:
o Ease of iPS cell from any cell of body.
o Cells can be stored for a long time.
 o Who regulates future use of iPS.

Core Ethical Principles in Responsible Research

1. Autonomy (Freedom to make intentional decisions independent of controlling
influences).
2. Non-maleficence (Obligation to do no harm).
3. Beneficence (Helping others and promoting good).
4. Justice (Impartial, equitable and appropriate treatment of all0.
 Stem Cells: Tissue Engineering
Role of Biomaterials In Tissue Engineering
- Tissue properties dictate design criteria.
- Avascular/small/tissues in vitro construct is feasible.
- 3D tissues = blood supply required early in development.
o In vitro bioreactors allow construct development
concurrently with vascularisation.
- Scaffolds, surfaces and microenvironments for cell growth.
- Biomaterials = mimic native tissue ECM.
- Provide space and biochemical environment to allow new tissue growth.
- Mechanics, chemical and biochemical interactions important.
- Design and Selection Criteria for Biomaterials in TE
o Good design may require compromise/optimisation.
o Design depends target tissue.
o “Biocompatibility” often claim but not universal
 Different synthetic properties have different reactions in different
tissue compartments.
o Novel materials are developing to become more compatible.
- Criteria for TE
o Biocompatibility.
o Mechanical properties for tissue target/site implantation.
o Biodegradability (just tissue remain.
o Suitable in vivo responses.
o Ability to be fabricated into desired structures.
o Cost-effective.
o Ability to be sterilised safely.
o Adequate stability and shelf-life.
o Promote desired cellular responses.
- Limitations and Challenges
o Foreign body reaction, acid release, toxicity, supply, sterilisation, cost and
reproducibility.
o Lack of knowledge of design criteria.
o Lack of predictability (in vivo response vs host performance).

Soft Macroporous Hydrogel Production - Hyaluronic Acid (HA)

- Prepare Cryogel Solution.
- Allow crystallization to occur.
- Crosslinking develops.
- Benefits
o Progens easily removed.
o 90% porous.
o Decrease toxicity.
 o Testable physical properties.
o Properties of biomaterials are easily matched to tissue stiffness.

Additive Manufacturing
- Handheld in situ biprinting to repair damaged articular cartilage in the knee.
- Repaired cartilage in defect sheep model in 8 weeks following implantation.
- Foreign Body Reaction (FBR)
o Occurs in response to implanted synthetic
materials.
o Limits biomaterial implant performance
and tissue regen.
o Mechanism
o Biomaterial absorb proteins.
o Neutrophils and macrophages interrogate
biomaterial
o Cells fuse to form giant cells and form
collagen encapsulation.

Surface Engineering Strategies: Proteins

- Layer-by-later (LbL) Assemblies
o PLGA scaffolds with LbL coating to provide blank slate.
- Nano-scale clustering of integrin-Binding Ligands
o Bind RGD onto cell surface to camo as “self” cell.

Surface Engineering for Multiple Biomolecule Delivery

- Porous Polymer Microspheres
- Porous structure + solvent.
- Controls slow release of growth factors.
o Alpha-MSH
o bFGF
- Slow release of factors reduces inflammatory cells present.

Tissue Engineering Scale Up for Clinical Use

- In vivo bioreactors for soft tissue engineering.
- Promote fatty tissue growth to reproduce breast tissue.

Summary
- TE strategies need to be tailored to tissue targets.
- Biomaterials selection and biocompatibility are application specific.
- Nano-/Micro-engineering can enhance outcomes.
- Success requires technical developments closely linked to clinical realities.
 Stem Cells: Disease Modelling and Drug Discovery
Gene Targeting and Editing: Essential Tools for Disease Modelling
- Principle of Gene Targeting by Homologous Recombination
- Process allows correction of a polymorphism or introduction
of a reporter gene.
- Gene editing tools  cut genomic DNA.
- Outcome depends whether single or double strand is cut.
o Single = gene knockout  disruption of faulty gene.
o Double = promoting recombination  correction of
genomic DNA.
- Using Stem Cell Disease Models  Evaluate Contribution of Specific Loci
- Polymorphism in LRRK2 and SCNA associated Parkinson’s.
- iPSC induced in people with Parkinson’s.
o Both genes are knocked out to investigate their
contribution.
- iPSC induced in Health subjects
o Gene mutation synthetically produced to
investigate effect of each mutation.
- Can analyse genome to determine specific mutation.
- Reporters of Development can help Identify iPSC Development
- Track SC  Lineage.
- Reporter Genes
- Fluorescent Proteins
o Identification and sorting without the need for substrate
o Weak expression
o Unpredictable
- Luciferase (Enzymatic)
o Sensitive plate-based assay (cell lysate)
o Good for small molecule screening.
o GBG and CBR offers potential assay of two
gene simultaneously.
- Beta-Lactamase
o Sensitive live cell imaging and FACS (plate-based assay with lysed cells)
o Green FRET substrate  blue upon cleavage.
- These reports guide our control of differentiation in vitro.

Principle of Stem Cell Technology in Disease Modelling

 - Steps: Recruitment  Somatic Cell Isolation  iPSC reprogramming  iPSC
differentiation  Comprehensive drug testing.
- Patient Derived iPSCs Limitations
o Reprogramming removes epigenetic markers.
o Difficult to model/correct polygenic diseases.
o Patient-derived iPSCs vs disease-free controls influence genetic backgrounds
and mask effects of disease-related genes.
o Gene editing on a common genetic background better approach (hESCs).

- Criteria for Disease Modelling using PSCs

Optimal Challenging
Inheritance Monogenic (fragile X Polygenic (autism)
syndrome)
Penetrance (Onset) High (cystic fibrosis) Low (Alzheimer disease)
Age of Onset Developmental disorder Late onset (Parkinson’s)
(down syndrome)
Mouse Model Not recapitulated in mice Good mouse model
Phenotype Cellular phenotype Pattern (tissue) formation
Tissue Accessible differentiation Inaccessible (multiple
(glycogen storage disease) myeloma)
- Many diseases are characterised by high penetrance are rare.
o Alzheimer’s diseases.
- Low penetrance may be polygenic and common.

Disease Modelling of Neurological and Neurodegenerative

- Neural Development and Treatment of Rett Syndrome Using iPSC
o iPSC from Rett Syndrome (RTT) patients, normal until 6-18 months.
o Wide variety of CNS deficiencies and autistic behaviour.
o RTT neurons have  less synapses, reduced spine density, smaller soma size,
altered calcium signalling, electrophysiological defects.
o Used RTT neurons to study effects of drugs on rescuing synaptic defects.
- Modelling Schizophrenia using iPSC
o iPSC from four SCZD patients differentiated into neurons.
o Most neurons  decreased neuronal connectivity and decreased neurite
number, decrease PSD95 protein levels, decreased glutamate receptor
expression, DNA array showed defects in cAMP and Wnt signalling.

Limitation of Current Practice in Drug Discovery

- Failure is due to lack of efficacy in humans or unexpected toxicity
- Likelihood of drug approval from start of clinical development = 10%
- Existing biological models unable to predict efficacy in humans.
o Poor models lead to poor selection of targets.
o Targeted discovery campaigns use reductionist approaches for
screening that provide limited or misleading biological data.
- Better biological models can help  target identification and during
discovery campaigns.
Targeted Drug Discovery vs Phenotypic Approach
- Reductionist Approach
o Simple in vitro assays for high throughput screening (HTS)
o Simple cell culture systems (dividing cell, overexpressed target)
o Tissue assays (small number of compounds)
o In vivo models (late stage)
o Assays that drive compound selection lack biological function.
o Common culture models are inadequate for drug discovery.
- hESC and iPSC better source of models for drug discovery.
o Mix different cell types together.
o Forms  tissues

Respiratory Health and Disease: Clinical

Perspective
Structure + Function of Respiratory System
- Function
o Transfer oxygen from the environment to RBC.
o Transfer CO2 from blood  air.
o Regulate acid-base balance.
- Structure
o Lower airway is divided into airways (bronchi) and
alveoli.
- Normal Spirometry
o Measures TLC.
o Tidal volume is normal breathing.
o FVC is the highest mark minus the lowest.

Changes to Lung Function and Ageing

- There is a decrease in lung function (22ml/yr) non-asthma and (38ml/yr) non-asthma.
- Increased decline in smokers.
- Mechanism of Decrease Function
o Ribcage becomes stiffer.
o Intercoastal muscles become weaker.
o Smoking + Asthma decrease lung elasticity.
- Decrease in FEV1

Lung Disease in Global Context

- 13.7% of deaths = TOTAL lung diseases.
- In countries with lower air pollution increased lung diseases.

Asthma Introduction
- Prevalence: 1/10 Australians
- Physiological Manifestation: The variable airflow obstruction.
 - Pathology: Inflammation = allergic reaction, Remodelling = Thickened basement
membrane  impossible to reverse.
- Hyperresponsiveness = changes in airway restriction excess to those who do not
have asthma.
- Treatment
o Anti-inflammatory treatment
works for eosinophilic asthma.
o Eosinophilic asthma is more
common.

Biological Mechanism of Asthma

- Inflammatory + Immunologic features of severe asthma.
- Diagnosis has been confirmed and co-morbidities addressed.
- Severe asthma = defined as asthma that requires treatment with high dose inhaled
corticosteroids + second controller and/or systemic corticosteroids to prevent
becoming “uncontrolled”.
- Occurs due to immunological reactions (IGE antibodies).

- Dupilumab:
o Mechanism = Anti IL-4 + IL13 receptors
(common alpha subunit between the two)
o Use = Good for sever eosinophilic asthma.
o Clinical Effects = Produce reduction in
exacerbations improvement in FEV1.
o Dose = 300 mg SC fortnightly.
- Tezepelumab
o Mechanism = Anti TSLP monoclonal antibody.
o Use = severe asthma
o Clinical Effects = Reduction in exacerbations
o Dose = 70 - 280 mg fortnightly.

Thunderstorm Asthma
- Asthma   Rhinitis
o Childhood allergic rhinitis leads to increase relative risk of asthma.
- Aerobiology in Asthma Exacerbations
o Allergic to internal make-up of pollen.
o Broken pollen grain is small enough to reach the lower
airways.
o Weather effect: whole pollen grains swept up into cloud 
moisture in the cloud fragments the pollen into smaller
pieces  dry ,cold outflows carry pollen fragments to
ground level, where people breathe them into their lungs.

Pathophysiology
- Inflammatory pathway:
o Allergic pathways triggered by IgE -allergen interaction.
o Can also be stimulated by environmental factors (smoking/pollutants).
COPD
- Causes/Risk Factors
o Smoking, air pollution, occupational dust and fumes, chronic asthma, impaired
lung growth and uncontrolled inflammation (alpha-1 antiprotease deficiency).
- Chronic Bronchitis: inflammation and excess mucus produced.
- Emphysema: alveolar membranes break down.
- Inflammatory Pathway (No Eosinophilic)
o IFN - gamma.
o CXC cytokines
o Mucin

Respiratory Health and Disease: Pharmacotherapy

Asthma
- Heterogeneous disease, characterized by chronic airway inflammation.
- Defined by respiratory symptoms: wheezing, shortness of breath, chest tightness,
cough.
o Vary over time and in intensity.
- Associated with airway hyperresponsiveness: constrict
too much and too easily.
- Usually reversible airflow limitation (bronchodilator
drugs).
- Airway Bifurcation
o As the airway progresses the airway gets smaller.
o Obstructed by hyperresponsiveness/mucosal
oedema.

Measuring Airway Obstruction

- Spirometry: measures volume and flow rate of air.
- FEV1: forced expiratory volume in 1 second.
- FVC: forced vital capacity.
o Asthma: reduced FEV1/FVC ratio.
o Sometimes FVC will be decreased.
o Usually reversible with bronchodilator.

Causes of Asthma
- Host Factors
o Genetics: atopy, airway hyperresponsiveness.
o Gender
 o Obesity.
- Environmental Factors
o Indoor/Outdoor allergens
o Occupational sensitizers.
o Tobacco smoke
o Air pollution
o Respiratory infections
o Diet
- Increase in immune disorders after the
decrease in vaccination.
- 15.3% in Victoria between 13-14 ears of age.

Asthmatic Inflammation
- Type 2 = TH2 Cell Mediated
o IL - 5: stimulate eosinophilic inflammation.
IL-13: stimulate class switching  IgE
o IL - 4: stimulateTH2 cells proliferation.
- Mast cells stimulate  smooth-muscle cell
bronchoconstriction.
- Responses to inhaled allergens.
- ILC2 cell stimulate IL-5 and IL-13.
- There is a blood to cell transition of TH2 cells.

Allergen Sensitization
- Produces memory B + T cells.
o IgE memory B-cell clonal expansion.
o Class switching to IgE.
- Theory: occurs due to epithelium damage.

Airway Remodelling
- Characterises asthma.
- Occurs in conjunction via many different mechanisms:
o Epithelial trans differentiation from ciliated
cells  goblet secretory cells results in
mucous hypersecretion.
o Epithelial  Mesenchymal transition results in
basement membrane thickening.
o Angiogenesis and vascular remodelling 
smooth muscle hypertrophy and hyperplasia.
o Neuronal sprouting  hyperresponsiveness.

Non-Type II Inflammation
- Non T2-type asthma:
o Obesity associated.
o Smooth muscle-mediated paucigranulocytic asthma.
o Smoking-related neutrophilic asthma.
o Adult onset.
- Non-Type 2 Inflammation
 o Mechanism established by TH17 and TH1 cells
o Stimulate neutrophils.

Therapeutic Strategies
- Past Strategies
- Asthma Cigarettes
o Contains atropine  bronchodilator.
o Hallucinogenic
o Narrow therapeutic window
- Heroin + Glycerin
o Cough suppressant
o Respiratory depression
- Current Therapeutic Strategies
o Prevent Development of Allergy
 Difficult
 Not all asthma of allergic origin
o Prevent or Reverse Airway Obstruction
 Airway smooth muscle contraction
 Prevent or reverse airway inflammation

Airway Smooth Muscle (ASM) Tone

- Occurs due to balance of relaxation and constriction.
- Constrictors  histamine, leukotrienes, acetylcholine.
o Gq protein receptors.
o Activate Rho Kinase
o Activate PKC
o Ca2+ oscillations activated MLC
Kinase.
o Phosphorylates Myosin Light
Chain.
- Relaxants  adrenaline, PGE2
o Gs protein receptors.
o Activate adenylate cyclase.
o cAMP  PKA
o Activate MLC Phosphatase.
o Does not allow Myosin Light Chain phosphorylation.
- Strategies for Bronchorelaxation
o Leukotriene receptor antagonists
o Anti-Histamines
o Muscarinic receptor

Beta 2 - Adrenoceptor Agonists

 - 1903: Adrenaline used.
- 1947: Adrenaline inhaled to have selective effects in lungs.
- 1948: Isoprenaline: becomes Beta selective
o Beta 1 side effects of increase heart rate and contraction.
o Along as Beta 2 bronchodilation.
- 1968: Salbutamol: became Beta 2 selective
o Beta 2 side effects of muscle tremors in skeletal muscle.

SABAs and LABAs

- SABAs = short acting Beta-adrenoreceptor agonists.
o Used when required (upon perception of bronchospasms).
o 2-5 min onset of action ‘relivers’.
- LABAs = long acting Beta 2-adrenoreceptor agonists.
o Reduce number of exacerbations.
o Benefit of chronic bronchodilation.
o LABA use associated with increased risk of exacerbations of death 
combined with ICS in single actuator ‘controller’.
- 2019 use of bronchodilators alone not recommended.
o Patients with mild asthma risk serious adverse events (not needed).
o Inhaled SABA has been first line treatment for 50 years (don’t see need for
additional treatment).
o Regular or frequent use of SABA is associated with adverse effects. (Beta
receptor downregulation, decreased bronchoprotection, rebound
hyperresponsiveness, decreased bronchodilator response, increase
hyperresponsiveness and eosinophilic airway inflammation.)
o Higher use of SABA is associated with adverse clinical outcomes.

Anti-Inflammatory Corticosteroids
- Mechanism of Action
o Binds cytoplasmic hormone receptor GR (glucocorticoid receptor).
o GR translocates to cell nucleus  modulate gene expression.
o Induce: anti-inflammatory genes, Beta2 adrenoceptors + apoptotic genes in
immune cell types.
o Suppress: Inflammatory enzymes, cytokines and adhesion molecule
expression.
- Inhaled Corticosteroids (ICS) decrease inflammatory cell no + activation, reducing
asthma symptoms.
- Oral Corticosteroids (OCS) used for most severe asthma, limited by systemic side-
effects.

New Frontiers
- Current therapies are only really effective for allergic/eosinophilic disease.
- Personalised/tailored treatment given sort of asthma.
- Potential  cytokine targeting mAbs, CXCR2 inhibitors.
 Respiratory Health and Disease: COPD
Normal Lung Function
- Lung Elastance: the recoil in which a lung bounces back after inflation. (balloon)
o Elastic Recoil.
- Chronic Obstructive Lung Disease (COPD)  decrease at lung elastance.

Lung Function Trajectories

- Determine projected lung function
over time based on risk factors:
o Smoking status = major risk
factor
o Age
o Height
o Lung size = major risk factor.
o Sex
o Co-morbidities
o Urban pollution = major risk factor
COPD Impairing of Lung Function
- Decreases lung function via:
o Destroying elastic recoil (via elastin molecule damage)
o Inflaming small airways.
o Causing increase mucus production.
- Currently irreversible making developing new treatments difficult.
- Bronchiolitis + bronchitis is inflammation of larger airways.
- Regenerative Medicine for Disease modification
o Re-Alveolarization will be easier than restoring small airways and
vessels.
o Due to  smooth muscle on leading edge of bud branching.

Drug Treatments
- Same drugs treat asthma as COPD.
o Bronchodilators  LAMAs and LABA combined.
o Steroids  used in conjunction with LABA/LAMA, other classes of anti-
inflammatory have not work and increase chest infection rate.
 Immunosuppressants in their action but COPD patients are
immunocompromised, big challenge.
o Vaccinations Recommended  influenza and haemophilus.
- Structural Damage vs Treatment Ability
o Difficult to treat due irreversible damage.
- Comorbidities
o Immune attenuation
o Immune dysregulation and tolerance
o Inflammo-pathology
o Oxidation, PTM and altered signalling.

COPD Degradation
1. Developmental and in utero hypoalveolarisation.
2. Epithelial dysfunction and EMT.
3. Increased inflammation.
4. Autoimmunity
5. Physical shear/tear.
6. Microcirculation death.
7. Oxidative and mitochondrial stress, biotransformation, nicotine addiction, catabasis,
Vit , EMT, Iron homeostasis, lung growth and repair, immunity and mucosal failure.
o 7 = drug targets.
- Exacerbations
o Viral/Bacterial
o Role of eosinophil
o PP10, O3, NO2 oxidative.
- Other co-morbid aspects of disease  recurring chest infection + cancer are more
“tractable” but don’t solve treatment problems.
Industry Problems
- Biggest lung diseases are not defined.
- Phenotypes are “treatable traits” are loose.
- Stratification is imperfect and new.
- Pathology-pathophysiology nexus is obscure and under trialled.
- “Modification” is an incipient concept.
o Phase 1: surrogates and biomarkers have very poor positive and negative
predictive utility.
o Phase 2: endpoints are blunt, lung function does not “see” small airway locus
of disease, imaging is nascent.
o Phase 3: trials on blunt endpoints large, costly, introduce multi-site
complexity and heterogeneity, slowly.
- Lung size and initial FEV1 may help predict future COPD disease and allow
aggressive early intervention.

Respiratory Health and Disease: Population Health

Population Health vs Individual Approach
- Individual
o Treat patients and conditions.
o Individuals often get better.
- Population Approach
o Value is based on papers that you publish.
o Peer review is important.
o Save millions of lives.
o Influencing policy and politicians.
o Creative mass media campaigns.
Tobacco Prevalence
- 5 million die annualy.
- 100mil in 20th century.
- 2nd biggest preventable risk factor.
- Causes 90% of COPD and lung cancer.
- Tobacco is a risk factor for 6 of the 8 leading causes of death.
- 1950s Spike
o Increase in advertising; branding of the behaviour.
o Production methods and delivery systems increase.
o Decrease cost, increase availability.
o Cultural shifts, peer behaviours.
o Addictive power of tobacco.

What Works in Tobacco Control

- Tobacco Control has saved 500,00 Australians.
- Coordinated approach from a global health treaty.
- More than 180 countries came together to:
o Decrease demand.
o Limit supply.
- Changes in policy result in decrease of smoking
prevalence.
- WHO uses an MPOWER method  Monitor, protect, Offer help, Warn, Enforce
bans, Raise taxes.

Effective Measures of Tobacco Control

1. Increase in price
- Effects the low income level more severely than the high income
earners. (2.6 low, 0.3 medium and 0.2 high).
2. Plain packaging:
- Reduces appeal of tobacco products.
- Increase effectiveness of health warnings.
- Reduce ability of retail packaging of tobacco products to mislead consumers about
harms.
3. Mass Media Campaigns
- Reduce smoking uptake among youths.
- Promote adult quitting.
- Reduce smoking prevalence in youths and adults.
 - Cost-effective method.
- Has a direct effect on viewers and indirect effect by increasing discussion of smoking.
4. Smoke-Free Policies
- Rely on justification that injurious to someone else to inhale smoke.

Critical of Industry Involvement in Public Health

- If given the chance to adhere to public health campaign, tobacco industry would put
their profits ahead of the safety of our population,
- Voluntary codes useless.

Tobacco Endgame
- Reduce consumption and availability of tobacco to minimal levels (2-5%)
whereby smoking is denormalised.
- Denormalised  Unaffordable.
- Remove all opportunities for advertising  plain packaging and counteract E-Cigs
loophole.

Approaches Proposed to get to Endgame

- Radical solutions include:
- Supply/Market
o Smoker license
o Raise the age limit
o Massive reductions in retail availability.
- Product Modification
o Mandate reduced/denicotinised cigarettes.
o Reduce palatability/appeal.
- Tobacco Company Liability
o Make them pay for their negligence.
o Occurred in USA and Canada.
- Barriers to Progress
- Biophysiological addiction to smoking.
- Political addiction to tobacco (no longer in Aus).
- Philosophical objections: individual liberty concerns.
- Insufficient trained, paid TC workforce.
- Powerful tobacco industry.

Respiratory Health and Disease: Interstitial Lung

Disease
Interstitial Lung Disease
- Characteristics of the Disease
o Broad heterogenous group of diffuse parenchymal lung disease (DPLD).
o Progressive fibrosis (scarring)  restrictive ventilatory deficit + decrease
oxygen diffusion.
 o Non-Specific symptoms of cough + dyspnoea  symptoms may be attributed
to other conditions + delay in diagnosis.
o Details History + Radiology provide initial basis for diagnosis.
 Histopathology complimentary
 MDM mandatory (expertise).
- Classification
o Known cause (drugs or collagen vascular disease related).
o Idiopathic interstitial pneumonia
o Granulomatous ILD
o Other ILDs
- Mechanism
- Lung injury + alveolar damage  telomere shortening, cell senescence, modified
respiratory microbiome  inflammation  abnormal lung repair  ILD.
- Diagnosis
- History: family history, medications, environmental and occupational exposures.
o Asbestos and mining
- Classification: classified due to presentation of the ILD.

Diagnostic Process
- Step 1: Laboratory Test
o Test blood levels
- Step 2: Pulmonary Function Test: Spirometry
o Restrictive Lung Disease: due to reduced elasticity of the lung
(decreased volume).
o Intrinsic = lung parenchymal disease.
 Shows increased levels of scarring  in decreased oxygen
diffusion in the blood.
o Extrinsic = pleural or chest wall, neuromuscular disease.
o All lung volumes are reduced but proportions are preserved.
o Decreased lung compliance.
o Low FEV1 and FVC but FEV1/FVC is normal or elevated.
- Step 3: Diffusing Capacity of lung for Carbon Monoxide (DLCO)
o DLCO is better predictor than spirometry.
- DLCO < 40% is indicative of advanced disease.
- Changes of >10% FVC or >15% DLCO indicates much higher mortality in patients.
- Desaturation during 6MWT: stronger prognostic predictor in IPF than PFT.

Pathophysiology
- Initiation:
o Epithelial damage
o Endothelial activation
o Immune-cell infiltration
o Inflammation
- Progression
o Fibroblast proliferation
 o Fibrocyte recruitment
o Epithelial-mesenchymal transition
o Ongoing epithelial damage.
- Failed Resolution
o Myofibroblast persistence.
o Altered matricellular interaction
o Perturbed epithelial repair
o Ongoing epithelial damage

Specific ILD: IPF (Cryptogenic Fibrosing Alveolitis)

- Most common idiopathic ILD.
- Median age = 66
- More men affected than women.
- Median survival is 3 years.
- Progressive dyspnoea + dry cough.
- Limitation to exercise tolerance and hypoxia.
- UIP on HRCT and histology (worst pattern on
lungs).
- Progression
o Very hard to predict.
o Heterogeneous.
o Previous underestimation of progression.
- Pharmacological Drug Treatments
- Nintedanib: slows decline and reduces exacerbations.
- Pirfenidone: slows decline and reduces all course mortality.
- Lung Transplant: limited younger candidates.

Asbestos Related Lung Disease

- Mined and used extensively in Australia 100 years ago.
- Created world-wide epidemic of asbestos related disease.
- Exposure
o Conc of inhaled fibres (fibre/ml)
o Cumulative exposure f/ml.year
o Occupational Exposure: gold and iron ore miners are at risk.
o Delayed Response: First published in 1927, 1962 in Aus but production did
not stop in 1983, complete ban in 2003.
- Asbestosis
o Diffuse pulmonary fibrosis, high degree of exposure, earlier than Cancer,
o Restrictive pattern on spirometry with reduced diffusion capacity.
o HRCT and UIP histopathology patterns.
- Lung Cancer
o Asbestosis is not a risk factor.
o Cohort has high tobacco use additive approaching a multiplicative effect.
- Medicolegal Considerations: asbestosis, lung cancer and mesothelioma as
compensable.
o Benign pleural disease may be compensable is associated with impaired lung
function.

Silica Related Lung Disease

 - Airborne silica dust is generated with several construction related activity.
- Crystalline Silica
o Exposure can cause multitude of disease.
- Risk Reduction: Control the Risk
o Minimise the generation of dust.
o Drills + Routers with dust collecting bags.
o Tools fitted with a water attachment to suppress dust.
o Fit large machinery with cabs that have air filtering system.
o Metallic shot, slag products or grit for abrasive casting, not sanding down wet
dusty work areas and processes.
o Clean up dust with industrial vacuum cleaner or by wet sweeping.
- Coal Workers’ Pneumoconiosis (Black Lung)
o Untreatable but preventable.
o Relationship between inhaled dust dose and fibrosis.
o Pure carbon, main constituent of coal dust, is largely inert.
o Organic and Non-Organic contaminants of coal such as
silica, iron, cadmium, lead, kaolin, pyrite and
polycyclic aromatic hydrocarbons all have pro-
inflammatory and carcinogenic properties.
o Crystalline silica is commonest contaminant and is
found in high quantities.
o Significant between CWP overlap and silicosis.
o Recommendations
 Exposure limits and monitoring protocols: standardise.
 Screening: national screening programs for at risk workers,
questionnaire, imaging, lung function testing.
 Medical workforce training.
 Centralised occupational lung disease register.

Pulmonary Rehabilitation
- Aim
o Reduce symptoms
o Optimise functional status.
o Increase participation
o Reduce healthcare costs making the manifestations of disease stable or
reversible.
- Components: Aerobic exercise, resistance training, flexibility training, muscular
fitness training.
- No consensus on optimal exercise intensity.
o Based on rated perceived exertion to 60-80% of peak work rate if results from
an exercise test are available.
o Program, modality and intensity of training must be individualised.
- Goals: improvement of exercise capacity, symptoms and quality of life.
o Protocols documented for COPD are effective in ILD.
o Oxygen desaturation is very common hence access to supplemental oxygen
should be available.
Lung Transplant
- Available if young and no other co-morbidities.
- Increase diffusion capacity.
- Diagnosis guides pharmacotherapy.

Respiratory Health and Disease: COVID-19

SARS-CoV2 Infection + Mechanism of Disease
- Infection Mechanism
1. Binding of SARS-CoV2 spike (S) glycoprotein to
angiotensin converting enzyme (ACE) 2, allows viral
entry via membrane fusions + endocytosis.
 Neuropilin (NRP1) may be an alternate
receptor.
 ACE2 has limited expression is respiratory
epithelium, found in gut enterocytes and
widely expressed in vascular endothelium
(linked with systemic disease).
 Protease activations is required (furin and transmembrane protease
serine 2 (TMPRSS2)).
2. Release of viral genome.
3. Translation of viral polymerase protein.
4. RNA Replication and sub-genomic transcription and translation of viral structural
proteins.
5. S,E and M proteins combine with nucleocapsid.
6. Formation of mature virus.
7. Exocytosis.
- Further studies have shown that heparan sulphate is a key determinant
as to the viral uptake + activation of SARS-CoV2.
- Has an RBD (receptor binding domain) that combines the ACE2 of the
cell membrane and the spike protein of the SARS-CoV2.
o SARC-CoV2 S and its RBD are main targets of vaccine.

COVID-19 Clinical Biology of infection

- Many report few or no symptoms but remain infected spreaders.
- Viral pneumonitis present >90% of symptomatic cases 3-5 days after infection
(spread from nose to lung).
- Around 80% of viral pneumonitis recover without specific treatment.
- Risk Factors (disease severity + poor vaccine response)
o Older men with hypertension, diabetes and obesity (highest risk).
o COPD but not asthma (ICS does not protect).
o Age - immunosenscencse.
o Immunodeficiency
o Poverty
o Low Vit D
o Ethnicity genes under infections.
- Disease Progression
o SARS-COV2 infects ACE2-expressing nasal epithelial cells in upper
respiratory tract.
o Virus infects ACE2-expressing type II alveolar epithelial
and patient exhibits pneumonitis (post-symptomatic).
o Severe disease involves disruption of epithelial/endothelial
barrier, complement deposition and hyperinflammation.
  Occlusion of vessels  further damage COVID attacks all cells that
display ace (all throughout body).
- 20% of patients deteriorate rapidly, 7-10 days after symptom onset.
- 25% of patients admitted to hospital will require mechanical ventilation, associate
with higher mortality.
- Children often don’t have severe disease  differential IgA secretion and platelet
response.
- Mechanism of Attack
o Vaccines attempt to treat S region of SARS-CoV2.
o Type I Interferons attack RNA-dependent RNA Polymerase.
- SARS directly interferes with anti-viral type 1 interferon induction in infected cells at
multiple levels.
- Leads to poor upregulations of type-1interferons (decreasing innate immunity).
- Unique ubiquitination and phosphorylation patterns observed.

Post-COVID-19 Effects
- Pulmonary Fibrosis
o Leads to increased stroke risk in heart.
o Induces life-long pulmonary fibrosis.
- Parkinson’s
o Neuronal complications may lead to late onset Parkinson’s.
o ENS is damaged in gastrointestinal symptoms (diarrhoea, nausea and
vomiting).

Neuronal Invasion
- ACE2 and TMPRSS2 expression in sustentacular cells.
- Maintain integrity of olfactory sensory neurons  infection leads to
loss of taste and smell.
- Olfactory epithelial cells also express NRP1 and couple provide
direct route to the brain.

Therapeutics
- Two proven therapies: dexamethasone + Remdesivir.
- Many disease modifying treatments are not recommended outside of clinical trials but
effects are being studied.
- Vaccines
o Convalescent serum and multiple synthetic antibodies in clinical trials.
o Domain Antibodies: based on the single chain structure of camel antibodies
(“humanized”).
- Leading Vaccines are mRNA or Adeno v vaccines that mainly don’t require freezing
(distribution ease (except JNJ)).
- Vaccine knowns
o Likely to be safe
o Mild-moderate flu-like smptoms and injection site pain.
o Not sterilizing
o Will not work well in elderly and vulnerable.
- Vaccine Unknowns
o Do they reduce progression of disease.
o Do they limit spread.
 o Long term safety.

Vaccine Hesitancy
- Key determinants to decrease hesitancy  vaccine properties, education on safety,
negative effects of social media.
Respiratory Health and Disease: Biological
Therapies for Respiratory Disease
Biological Therapy Definition
- A type of treatment that uses substances made from living organisms to treat disease.
- Often  Proteins: antibodies, hormones, growth factors.
o Could also be, nucleotides, sugars and lipids and synthetically engineered.
- Not  Vaccines, products containing cells
themselves.
- Mechanisms
o Receptor blockage
o Receptor downregulation
o Signalling Induction
o Ligand blockade

Production of Therapeutic Antibodies

- Produce monoclonal antibodies.
- Trending towards  humanising the antibody.
- Mechanism
o Inject antigen into mice.
o Isolate immune antibody forming cells.
o Fuse with tumour cells  hybridomas.
o Screened for production of desired
antibodies.
o Stimulate for clonal expansion.
o Monoclonal antibodies produced.
- Growing area of study.

Advantages to Biological Therapies

- Can target interactions not possible with small molecules.
- Specificity can be much higher  less adverse effects.
- Disadvantages
o Expensive and require injections.

Biological Therapies for Asthma

1. Anti IgE - Omalizumab
o Binds to free IgE, decreasing cell bound IgE.
o Decreases expression of high affinity IgE receptors.
o Decreases mediator release.
o Decreases allergic inflammation.
o Prevents exacerbation of asthma and reduces symptoms.
o Affective responses in 1/3 of patients.
 2. Anti-IL-5 Mepolizumab (GSK) Ruplizumab (Teva)
Anti-IL-5R Benralizumab (AZ)
o Bind to eosinophil and block IL release.
3. Anti-IL-4alpha Dupilumab.
o Interrupts signalling of IL-4 receptors, no signalling of il-13 when on its own.
- Suggested in high doses in controller form and T2 asthma.
- No similar therapies for COPD,
Biological Therapies for COVID-19
1. Neutralizing Antibodies
2. Blocking Antibodies
o Anti-IL-6/Anti-iL-6R not effective.
o Anti-IL-1 no clinical trial data.
3. Recombinant Cytokines
- IFN-Beta
o Asthmatic patients lack IFN-Beta  more susceptible to viruses that cause the
common cold.
- Questions we must ask:
o Does chronic respiratory disease affect risk of, SARS-CoV2 infection? More
severe COVID19 illness?
o Does treatment of chronic respiratory disease affect risk of (same diseases)?
o Can chronic respiratory disease treatments be re-purposed for COVID-19?
o Will biological treatments of COVID-19 affect the treatment of chronic
respiratory diseases?
Asthma
- Epidemiology
o 300 million asthma patients globally and prevalence is increasing
o 400 Australians die of asthma each year (2/3 are over the age of 55) - mostly
die in winter
o Asthma and reduction in mortality is a public health success story (through
the use of corticosteroids and beta agonists)
o Increase in developing countries
o Australia is the asthma capital of the world
o 15.3% between the age of 13 and 14
- Type of condition
o Inflammatory airway condition (mentioned above)
o Obstructive airway condition (mentioned above)
- Causes/risk factors
o Unknown
o But factors that influence and contribute to the development of asthma
 Host factors
 Genetic (atopy/allergy or airway hyperresponsiveness)
 Gender (before puberty boys are at high risk but this changes)
 Obesity
 Environmental factors
 Indoor allergens
 Outdoor allergens
 Occupational sensitisation
 Tobacco smoke
 Air pollution
 Respiratory infections
 Diet
 Hygiene hypothesis
- Diagnosis
o FEV1/FVC < 70%
o Measure FEV1 before and after a bronchodilator (beta-2-agonist) and if the
change is > 12% they are diagnosed
 Scalloping should improve with beta-2 agonist
- Pathophysiology/histology/inflammation
o Inflammation (type 2 inflammation)
 Usually in childhood-onset asthma: allergic asthma, exercise-induced
asthma, eosinophilic asthma
 Coordinated/mediated by TH2 (T helper cells)
 Damage to epithelium (from irritants)  epithelium cells detect this
danger  airway mucosa responds  dendritic cells (DC) detect
allergen with processes sent into epithelium  DC present the
allergen to native T cell  naïve T cell presents it to T-helper cell  T
cell travels to airways  release cytokines (IL-4, IL-5, IL-13)
  IL-5 attracts eosinophils
  IL-13 and IL-4 leads to class switching of B cells to produce
IgE (allergic immunoglobin) which can recognise the allergen
on the mast cell and activate mast cell  mast cells can
release bronchoconstrictors (histamine, cysteinyl leukotrienes,
prostaglandin D2)  bronchoconstriction
 New cell type can also contribute to type 2 inflammation which is
ILC2: IL-33 and IL-25 activate ILC2 cells  cause secretion of IL-13 and
IL-5  changes epithelial to produce mucous and activate eosinophils
o Inflammation (non-type 2)
 Usually in adult-onset asthma: obesity-associated asthma, smoking-
related neutrophilic asthma, smooth-muscle mediated
paucigranulocytic asthma
 Neutrophils and no eosinophils
 Mediated/coordinated by TH1 and TH17

o Airway remodelling
 Increased mucous due to changes in epithelial
 Normal ciliated cells transdifferentiate to become secretory goblet
cells to secrete mucous
 Thick layer of smooth muscle from hyperplasia and hypertrophy
(greater number of cells and cells larger in size)
 Thickening of basement membrane due to EMT (epithelial cells turn
into mesenchymal cells or fibroblasts which deposit ECM - collagen
and can lead to fibrosis)
 Neuronal sprouting which contributes to hyper-responsiveness
 Angiogenesis
- Allergic sensitisation
o Lots of memory cells
o Population of memory T cells from clonal expansion of the TH2 cells that
recognise the allergen – these are ready to recognise the allergen and
activate inflammation
o Population of memory B cells with IgE memory (and population of B cells
ready to produce IgE) to activate inflammation
- 3 characteristics/hallmarks of asthma (and definition)
 o Heterogenous disease characterised by chronic airway inflammation defined
by a history of repeated respiratory symptoms (wheeze, shortness of breath,
chest tightness and cough) and usually associated with airway
hyperresponsiveness and usually reversible airflow limitation with
bronchodilator drugs
1. Variable airflow obstruction (physiological manifestation)
2. Airway inflammation and remodelling (underlying pathological mechanism)
3. Airway (smooth muscle) hyperresponsiveness (condition of airway constriction
to doses of agonist or stimulus) – airway constricts too much and too easily so
airway is occluded
1. Airway inflammation
o Types
Non-eosinophilic Eosinophilic
(Normal eosinophil (Raised eosinophil count
count <1.9%) >2.0%)
Normal neutrophil Paucigranulocytic Eosinophilic asthma
count (<61%) asthma (no eosinophils
or neutrophils)
Raised neutrophil Neutrophilic asthma (no Mixed granulocytic
count (>62%) eosinophils) asthma
 Eosinophils and neutrophils are both types of granulocytes
o Most young people have eosinophilic asthma (TH2 inflammation driven by IL-
4 and IL-13)
o <20% of asthma is non-eosinophilic
o Inflammation and immunologic features of severe asthma
 Significant amounts of airway remodelling and mucous plugging and
airway inflammation (eosinophils)
- Treatment/therapeutics/management/pharmacological interventions
o Therapeutic strategies
1. Prevent development of allergy (difficult because not all asthma is of
allergic origin)
2. Prevent or reverse airway obstruction through 2 drugs
(pharmacotherapies)
 These drugs can be used in combination inhalers
(LABA/’controller’ WITH ICS/’preventer’)
 Asthma pharmacotherapy is an optimised adrenal gland
because both cortisol and adrenaline are released from there
and we have made glucocorticoid and adrenoceptor agonist
drugs
a. Relieve airway smooth muscle contraction
b. Prevent or reverse airway inflammation
a. Relieve airway smooth muscle contraction
 Airway smooth muscle tone – we need a balance between relaxation
and constriction of airways
Constrictors Relaxants
Description Substances that mediate Substances that mediate
constriction of smooth relaxation of smooth
 muscle through effect on muscle through effect on
the GCPR the GCPR
Bronchodilator
Mechanism GPCR  Gq receptor  GPCR  Gs receptor 
activate MLC kinase  activate adenylate cyclase
inhibit myosin light chain  cAMP  activate PKA
phosphatase   inhibit MLC kinase 
phosphorylate myosin activate MLC
light chain  constrict phosphatase 
smooth muscle dephosphorylate MLC 
relax smooth muscle
Types of Histamine Adrenaline (‘adrenergic’)
molecules Leukotrienes PGE2
Acetylcholine (ACh)
Drugs Leukotriene receptor Ventolin structure is
antagonist (e.g. based on adrenaline
montelukast)
Muscarinic receptor
antagonist (e.g.
Ipratropium)
Class Beta-2-adrenoceptor
agonist
 Development of beta-2-adrenoceptor agonist
 1947: inhalants - limited the SE to only the lung – limited SE of
beta-2 receptors in skeletal muscle which caused tremors
 1948: isoprenaline beta selective – limited SE b/c didn’t bind
to alpha receptor but could still affect heart and increase HR
(tachycardia)
 1968: salbutamol beta 2-selective (Ventolin) – first line
treatment
Class of SABA (short-acting- LABA (long-acting-
drug beta-2-adrenoceptor beta-2-
agonists) adrenoceptor
agonists)
‘Controller’
Types Salbutamol Salmeterol
Formoterol
Usage When required Reduce number of
(bronchospasm) exacerbations and
asthma attacks for
12 hours
Chronic
bronchodilation
Length of Rapid onset (2-5 mins) Variable onset
action Duration: >2 hours Duration: 12 hours
Note In very high doses, Associated with
tolerance could be increased risk of
 developed due to exacerbations or
down-regulation of death so is
beta-2 receptors combined with
inhaled
glucocorticoid in a
combination inhaler
Recommend In 2019, GINA recommended that controllers
(LABA) should be used over SABA because:
- Patients with mild asthma are at risk
of serious adverse events (fatal
asthma attacks)
- Inhaled SABA was used when asthma
was thought to only be
bronchoconstriction but now we
understand the inflammation etc.
- People like SABA because it provides
rapid relief of symptoms and a known
effect so often believe their asthma is
controlled when it is not
- Frequent use of SABA associated with
adverse effects such as down-
regulation of beta-2 receptors leads
to tolerance and decreased
bronchoprotection and can increase
allergic response (increase
eosinophils)
- Higher use of SABA associated with
adverse clinical outcomes (increase in
emergency department
presentations)
b. Prevent or reverse airway inflammation
 Anti-inflammatory corticosteroids
 A.k.a. inhaled corticosteroids (ICS) or preventers
 Combine them with LABA (long-acting beta-2 agonist)
 Effect of ICS (inhaled corticosteroids)
 Decrease inflammatory cell numbers and activation
 Reduce asthma symptoms, probability of exacerbation, risk of
hospitalisation and death
 Only effective for eosinophilic inflammation (not
neutrophilic)
 Oral corticosteroids
 Used for severe asthma or a rough patch
 Lots of systemic SE
 Development
 Started as hydrocortisone/cortisol (binds to both
mineralocorticoid receptor glucocorticoid receptor so led to SE
such as electrolyte balance, water retention and
 vasoconstriction)  prednisolone (only binds to glucocorticoid
receptor but still has SE)  inhaled glucocorticoid ICS such as
fluticasone or propionate (reduced side effects)
 Action/mechanism
 Binds cytoplasmic nuclear hormone receptor glucocorticoid
receptor (GR)  GR translocates to cell nucleus  modulate
gene expression 
o Induces
 Anti-inflammatory genes
 Beta-2-adrenoceptors
 Apoptotic genes in immune cell types
o Suppresses
 Pro-inflammatory genes
 Inflammatory enzymes and inflammatory
cytokines
 Adhesion molecule expression
o Biological medication
 Used for severe asthma and those with high eosinophilic type asthma
 Dupilumab
 Only used in those with high eosinophil types of asthma
 Anti-IL-4 and anti-IL-13 receptor antagonist
 Antagonises allergic pathways involving IgE and eosinophilic
inflammation stimulated by IL-4 and IL-13 cytokine pathways
(T2 pathways)
 Can improve lung function (FEV1)
 Tezepelumab
 Anti-IL-33
 Omalizumab (lecture 18)
 Mepolizumab (lecture 18) – AND explained in COPD part
 Benralizumab (lecture 18)
o Stepped approach to adjusting asthma medication in adults (Australian
National Management Handbook)
 There should be continuous monitoring and assessment at
each level
 1. Only a few patients should be on reliver medication (short acting
beta-2 agonists) as needed to relax airway muscle
 2. Most patients should be on a low dose regular preventer
medication (inhaled corticosteroids) – and a short acting beta-agonist
as needed
 3. Some patients should be on a low-dose combination regular
preventer which is an inhaled corticosteroid (and reliever as needed)
 4. Few patients should be on a higher-dose combination regular
preventer which is an inhaled corticosteroid (and reliever as needed)
 Severe asthma requires high dose inhaled corticosteroids plus
a second controller and/or systemic corticosteroids to prevent
it becoming uncontrolled – use of biologicals
o New therapies for asthma
  Cytokine targeting monoclonal antibodies
 Targeting non-type 2 inflammation
 Non-type 2 inflammation do not respond to corticosteroids
(steroid insensitive)
 CXCR2 inhibitors: CXCR2 receptor on neutrophil is a key target
as it helps the neutrophil access the airway – an inhibitor
would prevent the neutrophil entering the airway
o Results had no effect on exacerbations
 No therapy to reverse airway remodelling or reverse the fixed
obstruction
 Personalised medicine due to the heterogeneity of disease

Thunderstorm asthma
- Asthma epidemics are closely linked to aerobiological (pollen grains transported by
the air) events
- Major even on the 21st of November 2016
o Within 30 hours there were 3365 excess respiratory-related ED presentations
(44 to ICU) and 10 died
o Triggered by grass pollen - whole pollen grains are filtered by the upper
airway, but sub-fragments can get down to the lower respiratory tract - we
are allergic to the granular contents inside the pollen
o Weather
 Whole pollen grains swept up into the storm cloud  increase in
humidity/moisture in cloud bursts/fragments the pollen into pollen
grains  downdraft carries these pollen fragments to ground level
where people breathe them in
- Those at risk
o Biggest risk is having pre-existing asthma with hay-fever (allergic rhinitis)
o Risk of asthma onset with rhinitis (allergy/hay-fever)
 Childhood allergic rhinitis triggers asthma
 Lower risk as an adult unless adult has many symptoms
- Pathophysiology
o Allergic pathways triggered by IgE-allergen interaction (cognate pathway) –
Type 2 inflammation (mentioned above)
o Non-cognate pathways also involved such as the innate pathways which
recognise the pollen granules through IL-33 and IL-25 and activate ILC2 cells
(mentioned above)
 Mental Health: Introduction
Mental Health
- Definition: State of wellbeing, every individual realises his/her own potential, can
cope with the normal stresses of life, can work productively and fruitfully and is able
to make a contribution to her or his community.
- Good mental health is integral to human health and well-being.
- Absence of a mental disorder does not = good mental health.
o Not opposites (think of as overlap but not same category).

Mental Illness/Disorder:
- Definition: problems such as depression and anxiety (‘common/high prevalence
mental disorders’). Schizophrenia and bipolar (‘severe/low prevalence disorders’).
- People living with mental disorders can still achieve good levels of wellbeing and live
satisfying, meaningful and productive lives within the constraints of what can be
painful, distressing or debilitating symptoms.
- Disorders can result from stressful or traumatic experiences (but also occur without).
- Poor mental health that does not reach threshold for diagnosis = sub-threshold mental
disorders.
- Affect large proportion of Populations.

Social Determinants of Mental Health

- Mental health is shaped by  social, economic and physical environments.
- Compromise of these factors can result in social inequalities: poverty/deprivation,
lack of education, disease, cultural influences, discrimination.
- Population subgroups may be at higher risk of mental disorders  due to exposure to
unfavourable social, economic and environmental circumstances.
- Mental and physical health conditions emerge later in life, but originate early.
- Stressors
o Early childhood stressors can affects biological stress regulatory systems.
o Buffered by social support providing  loving, responsive and stable
relationships that build secure attachments between the child and caregiver.
o Cumulative exposure over time causes alterations in stress that affect the
physiology of: immune, gastrointestinal and respiratory, cardiovascular and
other systems.
o Stress-related behavioural responses  alcohol + drug abuse mental disorders
which can lead to alcohol and drug dependency.
o Lead to social and economic inequities.
o Inequitable mental and physical health outcomes.
o Actions that prevent mental disorders and promote mental health are essential
part of efforts to improve the health of the world’s population to reduce health
inequities.
Mental Disorder - Behaviour
- ‘Abnormal behaviour’ is shown by everyone at some point.
- Unusual behaviour is not necessarily abnormal.
- Abnormality is a subjective term (influenced by external factors).
- Abnormal Behaviour Criteria
o Rarity or very unusual
o Socially unacceptable or violates social norms.
o Perception or interpretation of reality is faulty.
o Person is distressed or not in control of their behaviour.
o Behaviour is inflexible, maladaptive, self-defeating or dangerous.
o The observations fit a syndromal pattern or a theory of disorder.
o Disability and/or disadvantage is present.
- Abnormal experience and behaviour does not indicate a ‘disorder’.

Anti-Psychiatry
- Social construct created by doctors.
- Diagnosis requires biological pathology (not present or known in
psychiatric disorders).
- Criteria for disorders  vague, subjective and open to
misinterpretation.
- Use of labels excludes those whose behaviour fails to conform to
society’s norms.
- Labels = social control and represent an abuse of power.
- Issues with medical and ethical integrity due to links with
pharmaceutical companies.

Disorder Criteria (DSM-5)

- Syndrome: clinically significant disturbance in an individual’s cognition, emotion
regulation or behaviour that reflects a dysfunction in psychological, biological or
developmental processes underlying mental functioning.
- Disorder Syndrome: associated with, present distress and disability.
- Disorder is not: expect culturally accepted response to a particular event, socially
deviant behaviour or a conflict between an individual and society unless due to a
dysfunction as above.
- Mental Illness Decision
1. Mental Illness  medical condition characterised by significant disturbance of
thought, mood, perception or memory, subject to certain exceptions outlined
below.
2. Exclusion  certain beliefs, behaviours or attributes which alone or in
combination cannot constitute a mental illness in absence of factors (sexuality,
religious and political beliefs).
- Diagnostic Value
o Descriptive value
 o Prompts consideration of treatments
o Evidence based care establishment
o Consider whole syndrome
o Predictive value
o Information retrieval
o Aids communication
o Public health planning and monitoring
o Source of concepts for scientific theory development and research.
- Does diagnosis refer to clear disease?
o No definitive biological test for psychiatric disorder.
o Many psychiatric disorders ‘overlap’, people meet several diagnosis.
- Standardised classification of mental disorders adults and children used by many
clinicians worldwide.
- Kept up to date (internet gaming disorders).

Other Factors Need for Treatment Planning (other than diagnosis)

- Other factors on top of diagnosis might be needed:
o Knowledge of contexts: personal, medical, situational, environmental,
social/occupational.
o Change/development of disorder over time.
- Importance of Culture
o Behaviour in one culture might be considered abnormal in another.
o Some disorders prove to be ‘cultural-specific’ (western culture: eating
disorders, chronic fatigue, South Asian: Koro)
o Koro might not be found in Western societies potentially because:
 Behaviour is not defined as abnormal
 Variation in human behaviour is not present  socially determined,
environmentally determined and requires gene-environment match to
be expressed.

Diagnosis and its Consequences

- Diagnosis marks formal status of “having a mental illness” being conferred”.
- Individuals react differently (often negatively).
- Stigma follows.
- Process of diagnosis can impact responses.
- Individuals can be reduced to their diagnosis.
- Individuals are not passive victims.

COVID-19
- Impact of COVID-19 on social determinants of mental health through: short + long
term changes in social engagement and employment + economic activity.
- Pandemic has had dramatic mental health impacts  increased anxiety, greater social
isolation (physical distancing policies introduced to control the disease).

Taking Action on Social Determinants

- Relationship between social adversity and mental health problems
appears bidirectional:
o Society adversity increases risk of poor mental health.
 o Having a mental health condition increases risk of poor social circumstances
and limited social connections.
- There is convincing evidence that policy making at all levels of governance and
across sectors can make a positive difference to mental health outcomes, and that the
empowerment of individuals and communities is at the heart of action on social
determinacies.

Mental Health: Population Health

Prevalence and Burden of Disease
- 2007 National Survey of Mental Health and Wellbeing
- Household survey of 9941 people
- Covering:
o Affective Disorders: depression, dysthymia, bipolar affective disorder.
o Anxiety Disorders: PTSD, social phobia, agoraphobia, generalized anxiety
disorder (GAD), panic disorder, obsessive compulsive disorder.
o Substance Use Disorders: alcohol and drug harmful use and dependence.
- Statistics
o 1/5 people experience a mental disorder in any 12 month period.
o 45.5% lifetime prevalence.
o Anxiety disorders are more common in females.
o Substance abuse disorders are more common in
males.
o Comorbidity is common - of 20% that have a
disorder, 8.5% have two or more disorders.
o Rates of mental disorders in Aboriginal and Torres
Strait Islander peoples are between 50% and 300% higher.
- 2010 Survey of High Impact Psychosis
- Covering: psychotic disorders (schizophrenia).
- Statistics
o Affect 0.45% of Australian 18-64 in any 12 month period.
o Eating disorders: anorexia nervosa affects 0.5% of young women, bulimia
nervosa: 1% and eating disorders not otherwise specific 2-5% of young
women.
- 2013-4 Child and Adolescent Mental Health Survey
- Household survey of parents and carers of 4-17 and 11-17 year olds.
- Statistics
o 1/7 4-17 year olds had mental disorder in
previous 12 months.
o ADHD most common followed by anxiety
disorders, major depressive disorder and
conduct disorder.
- Suicide in Australia
- Rising in Australia, higher in males.
 - Aboriginal rates of suicide are markedly higher.

Rates of Help Seeking

- Only 35% with a common mental disorder get help in 12 month period.
o 59% with affective disorders.
o 38% with anxiety disorders.
o 25$ with substance use disorders.
- Can take years before people receive effective treatment.
- Child and adolescent survey showed help seeking rates of 56%.

Impact of Mental Disorders - Personal

- 50% of people who experience a mental disorder have their first episode by age 18
and 75% by 25.
- Mental Disorders can impact: school, work, quality of life, relationships, connection
to and participation in the community and health habits.
Impacts of Mental Disorders - Burden of Disease
- Economic
o Total spending on mental health services in 2015-16 was $9 Billion.
o Funding groups  Australian government (35%), state/territories (59.8%) and
private health insurers (5.2%).
- Cost of Inaction
- Worldwide burden of mental health and substance use disorders, increased by 37.6%
between 1990 - 2010 (ageing + pop growth).
- Without action in prevention and treatment projected ageing of the Aus population is
likely to lead to an increasing burden.
- Failing to prevent, manage and treat mental disorders results in considerable costs,
impacting health system and broader society.

Australia’s Policy Response

- Context
- Considerable mental health care reform.
o Shift from institutional care  community rehabilitation.
o Use of non-government services.
o Recognition that mental health is equal in value to physical health.
o Support person-centred recovery.
- These reforms have brought change to way services are organised and delivered.
- Policies influences by conceptual frameworks:
o Understand of mental health and illness as a continuum from prevention
through early intervention and treatment to continuing care.
o Importance of promotion.
o Coordination and integration of care.
o Inter-sectoral collaborative care.
o Social inclusion.
o Recovery approach.
o Consumer and carer participation.
- National Mental Health Strategy
- Commenced in 1992.
- Main Purpose: ensure collaboration on policy and service development issues that
required a common focus.
 o Includes: national mental health policy (2008), NMH plan (2009), mental
health statement of rights and responsibilities (2012).
- Fifth National Mental Health and Suicide Prevention Plan
- Priority Areas

Interventions for Mental Health Problems

- Categories
- Universal health promotion (mental health literacy and stigma - beyond blue)
- Primary care or general health services (better access programs)
- Specialised clinical services (bed-based services)
- Community support sector (family and carer services)

Rates of Help Seeking

- Only 35% of people with a common mental disorder get help.
o 59% with affective disorders.
o 38% with anxiety disorders.
o 24% with substance use disorders.
- Can take years before people receive effective treatment.

Promotion and Prevention

- 1995 Mental Health Literacy Survey
- Household Survey - 2031 people aged 18-
74.
- 4th national mental health plan contained
following action items:
o Improve community and service
understanding and attitudes through
a sustained and comprehensive national stigma reduction strategy.
o Work with schools, workplaces and communities to deliver programs to
improve mental health literacy and enhance resilience.
o Develop further mental health information, national mental health data.
- Beyond Blue
o Independent not-for-profit organisations supported by federal, state and
territory governments.
o Established Oct 2000, initially focusing on raising awareness of depression
and reducing associated stigma.
o Added anxiety conditions in 2011.
 o Recently added suicide prevention.

Change in Prevalence
- Depression rates have grown from 1995 -
2011.
- Stress has decreased.
- Schizophrenia increased but 2003-4 was larger
than 2011.
- Role of Beyond Blue
o States which funded beyond blue had greater change than (low exposure
states).
o Awareness of beyond blue in high exposure states is twice the level of that in
low exposure states.
o High-exposure states had greater change in beliefs about some treatments,
counselling and medication and other benefits of help seeking in general.
o Dealing with the problem alone showed a greater decrease in helpfulness in
high-exposure states.
o Increases of having problem treaed like one in vignette.

Primary Mental Health Care Reforms

- Service use by people with common mental disorders
(image).
- ATAPS: access to allied psychological services
component of better outcomes in mental health care
program.
o Introduced in July 2001.
o Become part of flexible primary mental health
care funding pool.
- Better Access: to mental health practitioners through Medicare benefits.
o Introduced in Nov 2006.
- Both enable GPs to refer people with diagnosed common mental health disorders
which:
o Free/Low cost
o Evidence based
o Provided by allied health professionals.
o Time limited.
- Evaluation
o ATAPS and Better Access operate in a complementary fashion.
o Improve access to primary health care for people with common mental
disorders.
- Stepped Care Models
- Delivery of evidence-based services that increase or decrease in intensity according to
need:
o Start with low intensity.
o Involve systematic monitoring.
o Involve those who do not respond to stepping up to a higher intensity
treatment.
o May involve adding treatments of different modalities.
 - Benefits
- Less time from a professional.
- Less time from a patient.
- Lower cost.
- Lower therapist expertise.
- Self-help often used as first step: good effectiveness for self-help treatments and
effects on depression.
- Aims
o Retargeted the continuum of services to match patient need, moving from
reliance on matches care and face to face service delivery.
o Make more efficient use of workforce and technology.
o Emphasises early intervention and self-care, helping to shift the focus away
from acute and crisis intervention over time.
o Clinical guidelines have endorsed stepped care.
- Provides effectiveness benefits for anxiety and depressive conditions over usual care,
via early access to initial lower-intensity treatments.
- Some evidence gains in efficiency due to reduced therapist time required per patient.
- Some evidence for good levels of patient satisfaction with stepped care systems.

Need For Prevention

- PREVENTION IS BETTER THAN CURE.
-

Mental Health: Isolation and Loneliness

The Big Picture
- Social Isolation and loneliness can affect anyone at
any age:
- Two largest affected groups:
o 15-25 years
o 75+ years
- COVID-19 has exacerbated risks.
- Global megatrends have changes the world.
- People are more likely to flourish if they are socially
active and participate in local life.
o Those who don’t get our deteriorate mentally and physically  prone to
isolation loneliness and depression.
- 65+ aged people accounted for 2.8 million same-day hospitalisations and 1.8 million
overnight hospitalisations.
- Upwards of 80% of patients are elderly people.

Definitions
- Social Isolation: objective state of having minimal contact and
interaction with others and a generally low levels of
involvement in community life (voluntary or involuntary).
 - Loneliness: subjective unwelcome feeling of lack or loss of companionship of
emotional attachment with other people (involuntary).
- Two states are conflated but unrelated.

Myths about Loneliness

1. Loneliness is about social isolation
2. Loneliness is always bad
3. Mostly older people who are lonely
4. Loneliness is technology related
5. Loneliness means you need new friends
6. Feeling lonely is shameful

Prevalence and Duration

- Subjective states > difficult to measure.
- People unwilling to self-identify  shameful.
- Prevalence in Aus:
o 1.8 mill (9.5%) of Australian aged 15+ report a lack of social support.
o 25% report current experiences of loneliness.
o 51% report that they feel lonely for at least 1 day per week.
- Most incidents of loneliness last for less than a year, if it lasts longer it is likely to last
for three or more years.

Causes of Social Isolation and Loneliness

- Ageing brings with it experience of chronic and acute stresses and the cumulative
effects of these have been found to be predictors of the risk of isolation and
loneliness.
- Growing awareness of the impact on older people:
o Quality of neighbourhood environment becomes especially pertinent for older
adults given that they are likely to spend more time there, have mobility
restrictions and no longer drive.
- Older adults navigating their neighbourhoods that were many meaningful sites which
improved subjective mood. (Parks, cafes, shops and semi-private places, gardens and
driveways).
- Living alone and not being in a relationship are significant risk factors. Relationship
breakdown or single parents are also at risk.
- Feeling a disconnection from community and family are also risk factors, modern day
moving impacts older people.

Impacts and Strategies

- Impacts are  physiological, behavioural
psychological and societal.
- Some of the main consequences for human health
include:
- Benefits of Social Connectedness
o About quality not quantity.
 o Cessation of smoking.
o Abstinence from problem drinking.
o Adherence to medication.
o Healthy eating.
- The causative direction of these experiences has not been conclusively demonstrated.
- What is clear is that these experiences often co-occur and can be mutually
exacerbating of one another.
- Consequences of SI and loneliness
o Lost productivity
o Increased health care costs (mental + physical).
- Strategies: Significant body of research has identified several strategies to been
successful in fostering social inclusion and building social support:
o Introducing interventions as apart of wider strategic approach.
o Targeting specific groups of older people.
o Using existing community resources.
o Using volunteers to run programs.
o Using targeted and tailored approaches.
o Involving older people in the planning, delivery and evaluation of programs.

Interventions
1. Group: include peer teleconferencing, mutual support and discussion groups and
participation in arts and cultural activities.
2. One-on-One: direct provision of support services, counselling, provision of activities
such as foster grandparents scheme and home visiting.
3. Internet and Technology Based: interventions include online U3A programs and
new work on the use of avatars with older people.
4. Companion Animals: provide health benefits, mitigate impacts of social isolation
and loneliness such as improved cardiovascular health.
5. Government and other programs.
Other Factors
- Cultural and linguistically Diverse (CALD) communities and their culturally specific
needs.
- Psychographics of the generational cohorts.
- Access and capacity to navigate information in the 21st century.
- Capacity to understand and keep upw ithl ife int eh 21st century.

Conclusion
- Social Isolation and Loneliness are not isolated issues that can be successfully
addressed with a top down approach.
- Some of the related issues can be addressed with a holistic win/win approach
(malnutrition, transport, ageing in place, IT).
 Mental Health: Alcohol and Drug Abuse
Substance and Drug Use
- Refers to psychoactive substances that are taken to alter:
o Mood
o Cognition
o Behaviour
- Single definition is difficult due to:
o Cultural and moral values attributed to substances
o Differing perspectives
o Different legal meanings
o Intention of substance for other purposes.
- Classification of Psychoactive Drugs
- Depressants
- Stimulants
- Hallucinogens
- Synthetic drugs are new emerging psychoactive
substances (EPS).
Trends of Drug Use
- National Drug Household Survey AUS
- THC most commonly used illicit drug (increasing prevalence).
- Cocaine use increased.
- Meth 2nd most common illicit substance.
- Analgesics and opioids use reduced.
- US Highschool Survey
- 27.5% high schoolers smoked in previous 30 days.
- Low awareness to nicotine content.
- E-Cigarettes appealing to younger generations.
- Overall Trends
o Young people are older when they first try alcohol, cigarettes and illicit drugs.
o Smoking + drug use higher among people with mental health conditions.
o Cocaine use is city based.
o People in lower socioeconomic areas are 3.7 times more likely to smoke daily.
o People in remote areas twice as likely to smoke than in major cities.
- Priority population groups from NDSHS 2019
- Aboriginal and Torres Strait Islanders
- LGBTI communities.
- People experiencing psychological distress.
- Unemployed
- Lower education levels.

Drug Related Cost in Australia

- Years Live with Disability (YLD).
- Substance use disorders were a cause of high rates of YLD in
males.
- Alcohol use disorders are most common, drug abuse disorders 
cannabis and opioid.
- 2004-5 $56.1 Billion dollars spent on drug related cost.

Substance Use Disorder (SUD)

- Diagnosis is independent of quantity and frequency of use.
- DSM-5 “ clust of cognitive, behavioural & physiological symptoms indicating person
continues using substance despite related problems.”
o Impaired control
o Social impairment
o Risky use
o Pharmacological criteria: tolerance + withdrawal.
- Of that only 24% sought treatment.

Diagnosis of SUD DSM-5

- DSM-5 included gambling disorders.
- SUD
o Neutral term, loss of terms dependence/abuse.
o Range of disorders: mild  moderate  severe (chronically relapsing,
compulsive drug-taking or addiction).
- Nearly identical to DSM-4 criteria combined.
- Diagnosis
 - Mild 2-3 criteria
- Moderate 4-5 criteria
- Severe 6+ criteria
- Criteria
1. Often taken in larger amounts or longer period than intended.
2. Persistent desire or unsuccessful attempts to cut down or control.
3. Great deal of time to obtain/use/recover from effects
4. Craving//strong desire to use
5. Recurrent use resulting in failure to fulfil major role obligations at work, school or
home.
6. Continued use despite persistent or recurrent social or interpersonal problems
caused or exacerbated by use.
7. Important social, occupational or recreational activities reduced or given up due to
use.
8. Recurrent use in physically hazardous situations.
9. Use continued despite knowledge of physical or psychological problems caused or
exacerbated by use.
10. Tolerance, defined by either:
a. Need for increased amounts to achieve same effects
b. Reduced effect with continued use of same amount
11. Withdrawal
a. Characteristic syndrome
b. Same or closely related drug taken to relieve or avoid withdrawal.
- C’s of Addiction
o Compulsive - loss of control
o Continued use
o Consequences and harms.
- Not an acute condition with one off medical intervention.
- Chronic Relapsing condition which patient develops strategies for self-management
and clinician’s role is to care.
- Can be a time limited chronic condition.

Risk Factors for SUD

- AOD use in young people can be the norm, spectrum of
use.
- If there is an increase in use with an increase in age
there is an increase in risk of severity of SUD.
- Genetic RF
o 40-60% vulnerability
o Epigenetic and gene expression process unclear.
o Relates to frontal cortical grey matter
organisation.
o Physical and sexual maturation rates important.
- Early Brain Development RF
o “Brain plasticity” - remodelling, pruning, neuromaturation of the pre-frontal
cortex.
o Amplified motivation for reward + sensation seeking behaviour.
o Deficient control/inhibitory system.
o Exposure to AOD in social contexts.
 - Environmental RF
o Maltreatment + Early Stress: emotional, physical or sexual abuse.
o Parents: exposure to ATOD or antisocial behaviour, insecure attachments and
witnessing violence/abuse.
o Peer relationships: adoption of adult behaviours, use of caffeinated drinks,
friendships with dysregulated youths.
o Aboriginal/Torres Strait Islander background.

Rewards Pathway
- Drug and alcohol use uses these reward pathways
system as mechanism of action.
- Occur in sub-cortical areas of the brain.
- Ventral Tegmental Area (VTA) and Nucleus
Accumbens (NAc)
- GABA Inhibitory Feedback stimulates reward.

Relationship between AOD and Health

- 25.4% of people with 12-month substance use disorder had >1 class mental disorder.
- Dual Diagnosis
o Co-occurrence of mental health and substance use disorder.
o Narrow definition in MH literature of serious mental illness and substance use
disorder.
- Mental Illness and Substance use disorder often comorbidity occurs.
- People with MI experience more severe consequences of drug use than
general population.
- Substance use common cause of psychiatric treatment failure.
- Implications of Dual Diagnosis: Poor prognosis and bad treatment course.
- Anxiety and depression disorders are very prevalent with alcohol.
- Psychosis associated with cannabis and amphetamine use.
- Personality disorders associated with chaotic drug use (PTSD + alcohol to self-
medicate).

- Aetiology of Dual Diagnosis

- Reasons for Drug Use with MI

o Expectation of positive drug effects: habit, help sleep.
o Socialise: enjoy parties, fit in.
o Coping with negative effect: forget worries, predictive of substance use
disorder (SUD).
- Alcohol and Mental Illness
o Alcohol to manage symptoms of depression and anxiety PTSD.
 o Alcohol may worsen symptoms of depression.
o Alcohol is often seen with relapse of MI.
- Cannabis and Mental Illness
o Cannabis can lead to panic attacks.
o Long term cannabis use associated with depression and amotivational
syndrome.
o At high levels THC users may experience psychotic symptoms.
o THC has shown to be a risk factor for psychosis.

Treatment option for AOD and Dual Diagnosis

- Stages of Change (Image)
1. Pre -Contemplation
- Sowing seeds about change, related problem
to AOD.
2. Contemplation
- Motivation interviewing, encouraging
decision by increasing ambivalence and
precipitating decision.
- A lot of education + harm reduction strategies
can be put in place with contemplating.
- Staying engaged is chief strategy.
- Motivation Interviewing
o Come alongside rather than confront.
o Seek to get patient to self-articulate rather than lecture.
o Create a motivational matrix in which separates
emotions (limbic) from reasons (prefrontal) and
isolates different sections of the brain.
o Immediate reasons are going to have more effect in
behavioural changes.

Brief AOD Interventions

- FRAMES
- Feedback, Responsibility, Advice, Menu of options, Empathy, Self-efficacy.
- Treatment of SUD or “dependence”
o Cutting down may be sufficient.
o Abstinence
o Stopping (drug withdrawal can be dangerous, while awaiting therapy advise
gradual reduction).
o Staying stopped (challenges, difficulties with underlying MH conditions,
craving management, and relapse prevention).
- Medications that help staying stopped  tobacco, alcohol, opioids and stimulants +
cannabis.
Dual Diagnosis Complexity
- Requires care from BOTH MH services and AOD services.
- 3 Models of care
1. Integrated treatment  combined approaches for SUD and MH in single plan.
2. Serial treatment  treat primary condition first then secondary.
3. Parallel treatment  concurrent treatments in different settings.
- Best practice is integrated treatment.
- Difficult to complete parallel treatment due to separate MH and AOD sections.

Risk Minimisation Strategies

1. Supply Reduction
o Taxation
2. Demand Reduction
o Public health and education campaigns.
3. Harm Reduction
o Drink diary
o Controlled drinking
o Responsible drinking

Stigma Reduction
- Arguably the most important intervention for AOD.
- Barriers to Treatment & Care
o Impact on users, addicts.
o Expects to be judged, moralized, marginalised.
o Avoid presentation, therapeutic alliance and engagement.
o Concern about confidentiality.
- Impact on Clinical
o Addiction health as the lowest “hierarchy”
o Few clinicians choose as career
o Limited workforce

Mental Health: Brain Neurochemistry

The Brain
- Micro level: knowledge, cells + chemicals.
- Macro levels: emotion, memory, clinical knowledge.
- Cellular Players
o Cells: Neurons + Glia
o Chemicals: transmitters, modulators, growth factors.
o Structures: tracts and pathways, blood brain barrier.
- Neurons
o Transmit information.
 o Electrically excitable (depol lead to AP).
o Communicate via chem transmission.
o Rate of transmission critical (myelination + length of axon).
o One neuron will contact many others.
- Glia
o Astrocytes: star-like, physical guidance and biochemical support of neurons.
o Oligodendrocytes: myelination, one can myelinate multiple axons.
o Microglia: when activated behave like macrophages (phagocytic).

Chemical Transmitters
- Amino Acids
- Uniformly distributed
- Fast point-to-point transmission.
- Localised synaptic excitation and inhibition.
o Glutamate (excitatory), ionotropic  activate cation channels and
metabotropic (GPCR).
 Homo or hetero tetramers of 16 subunits.
 Kainite (pre-synaptic are inhibitory) all other excitatory.
o GABA (inhibitory), ionotropic  anion channels GABAa and metabotropic
GABAb receptors.
 GABAa  post-synaptic inhibition.
 GABAb  post synaptic inhibition (increase K+) or presynaptic
inhibition (reduced Ca2+) perm.
- Monoamines
- Expressed localised to small populations of neurons.
- Project in higher brain regions (emotion memory).
- Act on GPCRs (multiple subtypes, slow more diffuse transmission except
ACh nicotinic receptor).
- Associated with high level behaviours.
o Noradrenaline found in brainstem (pons + medulla).
o NA neurons in project to cortex, amygdala, thalamus,
hypothalamus and cerebellum.
o NA effects  arousal, mood, BP regulation.
o Dopamine has four main pathways: nigrostriatal  motor control, mesolimbic
 emotion and drug-induced reward, mesocortical  emotion,
tuberohypohyseal  control of pituitary gland.
o Receptors: D1 + D5 linked adenyl cyclase.
o D2, D3 and D4 activate K+ channels, inhibit Ca2+ channels and adenyl
cyclase.

 Expression Pattern:
 D1 and D2 found in areas of high DA innervation.
 D2 on DA neurons, inhibit DA synthesis and release (D2 antagonists
increase DA related activity.
 D3: limbic system.
 D4 weakly expressed cortex, striatum.
o Serotonin pathways resemble those of NA.
o 5-HT 2A-C Target of antidepressant and hallucinogenic drugs.
o ACh distributed widely
 o Muscarinic, responsible for most behavioural effects, arousal, learning, short-
term memory.
o Nicotinic, prejunctional, some involved in fast point to point transmission
(similar to amino acids).

Neurotrophic Factors
- Neurotrophins
- Brain-derived neurotrophic factor (BDNF)
- Involved in development.
- Mediate long term changes.

Blood Brain Barrier

- Difficult to isolate.
- Characters of BBB:
o Pericytes
o Tight junctions
o Astrocytes
- Challenges:
- Drugs act diffusely but brain functions via precise point-point connections.
- Receptor subtypes don’t map brain regions/pathways.
- Incomplete understanding of how neuron firing leads to behavioural effect.
- Incomplete understanding of how aberrations in signalling lead to mental illness.
- Relevant models of disease to test drug candidate.
- Blood brain barrier.

Mental Health: Medication used to Treat Mental

Disorders
Possible Sites of Drug Action
1. Synthesis of neurotransmitter and formation of vesicles.
2. Entering of Ca2+ to evoke neurotransmitter release.
 3. Neurotransmitter attaches to receptor, exciting or inhibiting postsynaptic neuron.
4. Reuptake of neurotransmitter to be recycled.

Schizophrenia
- Disease causing disruption of the mind.
- Affects 1% of population.
- Most often develops in young people (early teens - 30s).
- Symptoms
- Positive  Added (not good)
o Hallucination
o Delusions
o Disordered thinking
o Tend to be episodic.
- Negative  Taken away (not bad)
o Withdrawals
o Flattening of emotion
o Inability to experience pleasure.
o Reduced cognitive behaviour.
o Tend to last longer than positive symptoms.
- Diagnosis
- Not straightforward or quick.
o Other diseases also show psychosis.
- According to DSM -5:
o A month of psychotic symptoms
o 6 months of functional decline.
- Would treat a psychotic patient before any definitive diagnosis.
- It is NOT  split personality, contagious or a disease that makes a patient violent.
- Causes: Complex interplay of genetic and environmental factors.
- Pathogenesis: Malfunctions in dopaminergic neural circuits.
o Positive symptoms: activated by mesolimbic pathway.
o Negative symptoms: mesocortical pathway.
- Role of Dopamine
- Amphetamine causes release of dopamine and acute psychosis.
- Hallucinations are a side effect of L-dopa.
- D2 agonists cause affect like amphetamine, exacerbate schizophrenix symptoms.
- D2 antagonists block positive symptoms of schizophrenia.
- Complex:
o Positive symptoms: overactivity of mesolimbic pathway activating D2
receptors.
o Negative symptoms: underactivity of mesocortical pathway activating D1
receptors.
- Glutamate: NMDA receptor antagonists cause positive and negative symptoms.
- Neurodegeneration: might involve glutamate-induced excitotoxicity.
Drugs to Treat Schizophrenia
- First Generation = Typical = Conventional
- Produce motor side effects
- Affect positive symptoms only.
- E.g. chlorpromazine.
- Atypical
 - Reduced motor side effects
- Affect negative symptoms too.
- Use in patients that don’t respond to first generation drugs.
- Antipsychotics
- D2 antagonists or partial agonists.
o Antagonism of D2 receptors in mesolimbic pathway reduces positive
symptoms.
o Antagonism in other pathways  major side effects.
- Affects at other receptors alter the adverse effect profile and increase negative
symptoms.
- Antipsychotic Drug Side Effects
- Due to the antagonism of D2 receptors outside mesolimbic pathway.
- Acute Dystonias
o Involuntary movements, restlessness, protruding tounge.
o Resemble Parkinson’s disease.
o Blocked of D2 receptors in nigrostriatal pathway.
o Reversible
- Tardive Dyskinesia
o Involuntary movements of face tounge trunk and limbs.
o Develops slowly
o Increased D2 receptors in corpus striatum?
o Irreversible
- Major side effects of antipsychotic drugs
- Endocrine effects:
o Normally DA acts on D2 receptors to inhibit prolactin secretion by pituitary.
o Anti-psychosis therefore increase plasma protein (breast swelling, pain,
lactation).

Convention Antipsychotics
- Chlorpromazine
- D2 antagonist
- But also:
o Anticholinergic
o Antihistaminergic

Atypical Antipsychotics
- Olanzapine
- D2 antagonist but also 5HT2a antagonist.
- 5HT2a antagonism in striatum. (enhances DA release to reduce extrapyramidal SE).
- 5HT2a antagonism in mesolimbic pathway (combines with DA antagonism to
improve positive sysmptom).
- 5HT2a antagonism in mesocortical pathway (enhances DA and glutamate release,
improves negative symptoms).

Limitations: Antipsychotic Drugs

- 30% of patients do not respond.
 o Clozapine works for some of these.
o Causes agranulocytosis in 1-2% of patients that potentially can be fatal.
- Extrapyramidal motor effects (tardine dyskinesia).
- Antipsychotic malignant syndrome.

Depression
- An affective disorder (affects mood rather than cognition).
- Symptoms:
o Low mood, self-esteem, lack of motivation, anhedonia, loss of libido, loss of
appetite, sleep disturbances.
- High risk of suicide.
- Unipolar Depression: reactive depression (associated with stressful life event),
endogenous depression (unrelated to external stress).
- Bipolar Affective Disorder: depression alternating with mania (over weeks).
- Theories of Depression
- Monoamine Theory
- Deficit in 5HT and NA.
o Tricyclic antidepressants: block NA + 5HT uptake and increase mood.
o Monoamine oxidase inhibitors: increase NA and 5HT stores, increase mood.
o Reserpine: inhibits NA and 5HT storage, decreases mood.
- Simple monoamine theory cannot be complete.
- Effects of antidepressants on transmitters is rapid, but effects on person take weeks to
manifest.
- Secondary, adaptive changes are important.
o Tropic Effects and Neuroplasticity
 Antidepressants raise BDNF levels.
 Antidepressants reduce glutamate release, suppress NMDA receptor
function.
o Neuroendocrine changes
- Monoamines are agents of these long term trophic changes.

Classes of Antidepressant Drugs

- Inhibitors of Monoamine Reuptake
o Selective serotonin reuptake inhibitors (SSRIs)
o Tricyclic antidepressants
o Mixed 5HT and NA reuptake inhibitors
o NA uptake inhibitors
- Monoamine Oxidase inhibitors (MAOIs)
o Irreversible, non-competitive, non selective.
o Reversible, MAO-A selective
- Monoamine receptor antagonists
- Mechanism of Action
- Not completely understood.
o SSRI
 Increase of 5HT at synapse
 Chronic treatment desensitisation of presynaptic 5HT1A.
 Leads to sustained increase in 5HT in forebrain.
 Long term trophic changes bring about antidepressant effect.
Adverse Effects/Limitations
- SSRIs
o Nausea, anorexia,, loss of libido, failure of orgasm.
o Probably due to stimulation of wrong 5HT subtype receptor. (or right subtype
but in wrong region).
- Tricyclic Antidepressants
o Anticholinergic effects.
o In overdose can cause confusion, mania and ventricular arrhythmias.
- Limitations of Antidepressants
- Slow onset
- Better for moderate to severe depression (less effective for mild).
- Degree of benefit may be limited, varies between patients.
- Adverse effects
- Increase suicidality in adolescents.
Mental Health: Suicide Prevention Population-based
Interventions
Suicide Epidemiology Australia
- Males account for ¾ of suicides.
- Increasing in prevalence at a steady rate.
- Most common between the ages of 20-60.

Risk Factors for Suicide

Suicide Prevention Interventions

- Universal
- Target whole populations.
- Aim  favourably shift risk (and protective) factors
across the entire population.
- Can either impact on some aspect of social
environment or promote resiliency in individuals
within the population.
- Target particular risk factors without identifying
those in the population who have risk factors.
o Restricting access to lethal means of suicide.
o Media campaigns designed to promote help-seeking.
- Selective
- Target subgroups in population who exhibit risk factors that predispose them to
suicidal thoughts/behaviours.
- May directly/indirectly target people with mental health problems as an at-risk group.
o Specific pharmacological treatments for affective disorders.
 o Interventions that aim to better equip GPs to detect, diagnose and manage
depression.
- Indicated
- Target people who are exhibiting suicidal thoughts or behaviours.
- Often people are identified through screen programs of clinical presentation.
o Face-face of telephone crisis services.
o Cognitively-based therapies to improve problem solving and coping skills.
o Crisis-oriented interventions aimed at ensuring individuals have immediate
access to services in event of suicide risk.

Preventing Suicide in Boy and Men

- Males dominate suicide statistics:
o More likely to choose lethal means.
o More likely to use drugs and alcohol.
o More likely to withdraw in the face of stress.
o Less likely to seek help.
- Masculinity: socially constructed gender ideal for boys and men.
- Promotes, self-reliance, stoicism, independence and avoidance of negative emotions.
- These qualities are often positive, but run counter to at-risk boys and men seeking
help.
- When they do seek help, the help may not meet their needs.
- Masculinity Interventions
- Universal and Selective overlap: Designed to increase help-seeking, delivered to all
males in workshops/media campaigns.
- Indicated: Ensure that when boys and men do seek help their needs are met.
o Man-Up Documentary
o Found a significant increase in likelihood of help-seeking behaviours.
o Not enough seek help when at risk.

Intervention List
- Breaking the Man Code
o Intervention status: Existing
o Target group: Year 10-12
o Setting: School
o Format: Workshops
o Partners: Tomorrow Man, Gotcha4Life
o Trial lead: Kylie King
- Ahead of the Game
o Intervention status: Existing
 o Target group: 12-17 year old males and their parents and coaches.
o Setting: Sports clubs
o Format: Workshops and online modules
o Partners: Movember
o Trial lead: Stewart Vella
- Mates in Construction
o Intervention status: Existing
o Target group: Construction workers
o Setting: Male-dominant industries
o Format: Integrated program of training and support
o Partners: MATES in Construction
o Trial lead: Tony LaMontagne, Tania King
- Conversation about Suicide
o Intervention status: Needs modification
o Target group: Older men
o Setting: Men’s Sheds
o Format: Workshops
o Partners: MHFA, Victorian Men’s Shed Association
o Trial lead: Nicki Reaveley, Amy Morgan
- Media-based Male Suicide Prevention Campaign
o Intervention status: New
o Target group: Boys and Men
o Setting: Community
o Format: Digital and Traditional Media
o Partners: Heiress Films, Gotcha4Life, Everymind
o Trial lead: Jane Pirkis, Simon Rice
- Specialist Lifeline Services
o Intervention status: New
o Target group: Male Lifeline Callers
o Setting: Lifeline
o Format: To be finalised, likely to include a choice of male/female trained
telephone crisis supporters and modalities and male centred messaging.
o Partners: Lifeline
o Trial lead: Simon Rice, Jane Pirkis
- Mantle Health + Men in Mind
o Intervention status: Existing
o Target group: Professional Men
o Setting: Psychologists, deliver services to professional men via a secure
phone/video-link format.
o Format: Workshops
o Partners: Movember, Mantle Health
o Trial lead: Zac Seidler

Conclusion
- Decreasing suicides in men and boys would go further than any other single approach
to Prime Minister’s goal of working towards zero suicides.
- No single strategy stands out above others, combinations of evidence-based
strategies should be assessed.
 - Suicide is a major public health problem and certain groups at heightened risk.
- Males are a subgroup in which suicide risk is unacceptably elevated.
- We have insufficient knowledge about what works, therefor constant evaluation is
required to find out what is helpful or harmful.

Mental Health: Socioeconomic and Social influences

Spending on Mental Health
- Expenditure per person on MH in Australia has
increased by over 30% and is now more than $370 per
head or $9 billion nationally.
- Why has there still been a steady increase/not a
decrease in MH.
- Considerable efforts have not brought a decrease.

Social Determinants
- Health problems are more frequent in societies which
have higher income inequality.
- Increased inequality  higher psychological distress
 higher rates of depression, anxiety and suicide.
- Inequality affects social relations and behavioural
outcomes (loneliness and roll on emotional well-
being).

Distribution of Psychiatrist/Psychological Services

- More psychiatrist services are found in areas which don’t need them.
- Inequitable properties of MH service distribution.
- Usage is three times higher in most socioeconomically advantaged
quintile.
- Psychological distress is three times higher in most disadvantaged
quintile.
- STARK MISMATCH OF SERVICE DELIVERY AND
NEED.

Drug Therapy in MH
- Therapy is more expensive than medication but less effective.
- ADM Study: In a group of 8 people: 3 in placebo will recover and 4 in ADM will
recover.

Clinical Iatrogenesis
- Clinical Iatrogenesis: when pain, sickness and death result from medical care.
- Social Iatrogenesis: when health policies reinforce an industrial organization that
generates ill-health.
 - Cultural Iatrogenesis: symbolic when medically sponsored behaviour and delusions
restrict the vital autonomy by undermining their competence in growing up, caring for
each other.
- High SES Areas: typically of good quality, interdisciplinary, participative and
biopsychosocial care. Commonly lead to benefits for those receiving.
- Lower SES Areas: limited psychotropic approach to their care and by virtue
medicalisation, be discouraged from application of their self-help strategies.
o Given limited effectiveness of this bio-medical approach, the drop-off in self-
help effort may, for many, outweigh the benefits of medicalisation.
- Since people with mental health problems in lower SES areas greatly outnumber those
in higher SES areas, the overall population impact may be roughly neutral.
- Need an increase in professional care compared to decreased self-care.

Key Points
- Australia’s mental health care delivery system, considered in terms of equity is an
abject failure.
- An inverse-care-law applies, in which three times as many national-insurance funded
psychological services are delivered in the least disadvantaged fifth of Australia.
- Tele-health, now standard practice in COVID-19 may fare no better.

COVID-19
- Government transfer payments rapidly instituted early in 2020 may decrease
economic barriers to treatment.
- Stresses may increase rapidly for these people and communities and effective mental
health care will not be there for them.
- The need to get helpful mental health interventions delivered in an equitable and
empowering way has never been greater.

Principles of Recovery Oriented Mental Health Practice

- Recovery is not synonymous with cure.
- Recovery in context of Mental Illness:
o Gaining and retaining hope
o Understanding ones abilities and disabilities
o Personal autonomy
o Social identity
o Meaning and purpose in life
- Personal Recovery: a unique process of changing one’s attitude, value, feelings.
Living a satisfying and hopeful life event with limitations caused by the illness.
- Development of new meaning and purpose in one’s life as one grows beyond the
catastrophic effect sof mental illness.