Cellular Responses to Stress

and Injury
Ms. P Manyau
School of Pharmacy
University of Zimbabwe
Objectives
• Cellular responses to stress
• atrophy, hypertrophy, hyperplasia, dysplasia, metaplasia
• Cell injury, death and senescence
• Major causes of cell injury
• Reversible and Irreversible Ischaemia
• Hypoxia
• Cell necrosis
Introduction
Introduction
• Essentially all diseases exert their effects on the smallest living unit in
the body – the cell.
• When the cell is in stressful conditions it undergoes adaptive changes
in order to survive
• If stress continues adaption becomes maladaptive and drive the disease
process, and eventually cell death occurs
• Adaptions occur through cell extracellular and intracellular signalling
mechanisms
• Signals cause changes expression in gene expression patterns
• When chemical signal is removed gene expression reverts back
Types of Adaptive Changes
Atrophy
• Decrease in cell size
• Oxygen consumption and cellular function
is reduced
• Fewer structures in the cytoplasm
• Cell size (esp muscle) is related to workload
• As workload declines so does O2 consumption
and protein synthesis which leads to atrophy
• Muscle atrophy occurs by the following
mechanisms
• Increase in catabolism e.g. Proteolysis
(ubiquitin proteasome system)
• Decreased anabolic processes and cell death
Causes of Atrophy
• Disuse e.g. limb in a cast
• Denervation – paralysis
• Loss of endocrine stimulation
• If a hormone is responsible for
function of an organ, if that
hormone is removed the organ will
atrophy e.g. ovaries after
menopause
• Inadequate nutrition
• Ischemia or decreased blood flow
Hypertrophy
• Represents an increase in cell size
and increase in functioning tissue
mass –
• It is the result of increased
workload imposed on the body
commonly seen in cardiac and
skeletal muscle Can occur as a
normal adaptive process
• Or a compensatory hypertrophy in
the case that a piece of tissue is
removed and the rest of the organ
hypertorphies to compensate
Mechanisms of Hypertrophy
• Signals which initiate
hypertrophy are related to
• ATP depletion because of
increased workload
• mechanical forces such as
stretching of muscle fibres
• hormonal factors
Cardiac Remodeling – the classic example
• Biomechanical mechanisms
• Increased vascular resistance increases workload of the heart
• Internal stretch-sensitive receptors for biochemical signals and membrane
bound receptors (growth factors) stimulate specific pathways for growth
• Neurohormonal mechanisms
• Released in response to decreased cardiac output
• Release of hormones, growth factors, catecholamines, inflammatory mediators
which control myocardial growth
• Cardiac output continues to decrease due to increased peripheral resistance in
reduction in left ventricle size
• Tissue adaption reaches a limit eventually
Concentric and Eccentric Remodeling
Concentric Remodeling – Physiologic
adaption Eccentric Remodeling – Maladaption
Cellular Pathophysiology
• Concentric remodeling is the primary response to wall stress is
myocyte hypertrophy, elongation and cell death
• Imbalance between myocyte death and regeneration by progenitor
cells
• This process leads to remodeling, the eccentric type
• Eccentric remodeling worsens cardiac load and perpetuates the
deleterious cycle
Hyperplasia
• Refers to an increase in the number of cells in an organ or tissue
• It occurs in cells that are capable of mitotic division e.g. intestinal,
epidermis, glandular tissue
• Certain cells like neurons rarely divide and have little potential for
hyperplastic growth
• Hyperplasia occurs in response to an appropriate stimulus.
• Physiologic
• Non-physiologic
Physiologic Stimuli
• Hormonal and compensatory
• Hormonal includes breast and uterine enlargement during pregnancy from
oestrogen stimulation
• Or regeneration of an organ after partial removal
• Non-physiologic hyperplasia are due to excessive hormonal/ growth
factor stimulation and are not compensatory
• Excessive oestrogen production can result in endometrial hyperplasia
• Benign prostatic hyperplasia is thought to be related to the action of
androgens
• Warts are the result of hyperplasia caused by papillomaviruses
Metaplasia
• Represents a reversible change in which one adult cell type is
replaced by another adult cell type
• Involves reprogramming of undifferentiated stem cells that are
present in tissues undergoing metaplastic changes
• Usually occurs in response to chronic inflammation/ irritation which
allows for substitution of cells that are better equipped to survive
• The conversion never oversteps the boundary of that tissue cell type e.g. an
epithelial cell type can be converted to another epithelial cell type but not
connective tissue
Metaplasia
• Adaptive substitution of
stratified squamous epithelial
cells for ciliated columnar
epithelial cells in the trachea of a
smoker
• Squamous epithelial cells survive
better, but protective effect of
ciliated cells is lost
• Leads to stasis of mucus and
particles in the trachea increasing
susceptibility to infection
Dysplasia
• Characterised by deranged cell
growth of specific tissue that Dyplasia in Cervical Cancer Lesions
results in cells that vary in size,
shape and organisation
• Associated with chronic irritation
and inflammation
• This pattern is most commonly
encountered in squamous cell
epithelium of the respiratory tract
and the uterine cervix
• Dysplasia is strongly implicated as a
precursor of cancer
Introduction
Cell Injury
• Cells can be injured in may ways
• Cell injury and death are ongoing processes, and in a healthy state they are
balanced by cell renewal
• The extent to which injury is reversible depends on intensity and duration of injury
and type of cell
• Other variables include blood supply, nutritional capacity and regenerative capacity
• Causes of cell injury have been grouped into 5 categories
• Injury from physical agents (trauma)
• Radiation injury
• Chemical injury
• Injury from biological agents (bacteria and viruses which produce toxic substances)
• Injury from nutritional imbalances
Injury from Physical Agents
• Mechanical forces: these split and
tear tissue, injure blood vessels and
disrupt blood flow
• Extreme temperatures damage cells,
organelles and enzyme systems
• Burns induce disrupt cell membranes,
cause vascular injury, accelerate
metabolism, inactivate temp sensitive
enzymes
• Extreme cold increases blood viscosity
and induces vasoconstriction may result
in hypoxic injury. If cells freeze ice
crystals may rupture cells
Radiation Injury
• Electromagnetic radiation
comprises a wide spectrum of
wave-propagated energy
• Ionising radiation is high
frequency
• Ionising radiation produces free
radical species which destabilise
molecules in critical cell
components
• Can damage DNA and lead to
cancer
Ionising Radiation
• Damage due to radiation is dose-dependent
• Chronic occupational exposure involves exposure to low amounts of
radiation which increase risk for developing cancer in the future
• Acute cell injury can manifest as
• Initially there may be vasodilation which presents as erythema
• Damage to blood vessels that supply irradiated tissues. Swelling, disruption of
cell organelles which affects function, alterations in cell membrane
• Very high doses can lead to cell necrosis, scarring of tissue and organs
exposed
• UV radiation causes damage to DNA in the skin
Non-ionising Radiation
• Includes infrared light, ultrasound
and microwaves
• Low frequency non-ionising radiation
is used in radiowaves, television
waves, household appliances etc
• Unlike ionising radiation which can
break chemical bonds, this causes
vibration of atoms and molecules
• The energy generated in converted to
thermal energy
• Damage from these types of waves is
rare, however they present as burns
Chemical Injury
• Chemical agents injure the cell by blocking enzymatic pathways,
disruption of osmotic and ionic balance, corrosion of membranes by
strong acids and bases
• Drugs e.g. antineoplastic agents can kill cells by disrupting the cell
cycle, and inducing apoptosis
• Some drugs can have toxic metabolites e.g. paracetamol has metabolites
which are reactive and bind and damage liver cells
Mechanisms of Injury
• Free radical Injury
• Cell injury involves formation of free radicals
• Involves formation of reactive molecular species with unpaired electrons in
the outer orbit
• Types of injury that generate free radicals include ischaemia reperfusion
injury, chemical and radiation injury, cellular ageing, microbial infection and
inflammation
• Hypoxic cell injury
• ATP depletion
Free Radical Injury
• Most are derived from O2.
reactive oxygen species (ROS)
• Superoxide, peroxide hydroxyl
radicals
• They interact with cell
components (carbs, protein,
lipids), thereby damaging cell
components, inactivating
enzymes and damaging nucleic
acids
Antioxidants
• These are molecules with the ability to quench free radicals
• Examples include:
• Molecules: Carotenes, tocopherols, ascorbate, glutathione, flavonoids
• Enzymes: superoxide dismutase, catalase, glutathione peroxidase and
thioreductase
• Micronutrients selenium and zinc
• Superoxide dismutase converts superoxide (O2-) to H2O2 (hydrogen
peroxide)
• Catalase catalyses conversion of H2O2 to water
Diseases associated with Oxidative Stress
• Oxidative stress is thought to have
an important role in the
development of cancer
• The endothelial dysfunction that
contributes to development and
progression of cardiovascular
disease is thought to be caused by
oxidative stress
• Oxidative stress has been
associated with age-related
functional decline
RECAP
1. What are the 5 ways cells respond to stress
2. State 3 mechanisms of cell injury
3. Name 1 enzyme and 1 chemical antioxidant
4. What is oxidative stress
Hypoxic Injury
• Hypoxia deprives the cell of O2 and interrupts oxidative metabolism and generation of ATP.
• The time taken to produce irreversible damage depends on the metabolic need of the cell
and the duration of O2 deprivation
• The heart, kidney and brain require large amounts of O2 to function and are prone to hypoxic injury.
E.g. it takes 4-6 minutes to cause permanent damage to brain cells, proximal tubule cells can survive 20
minutes of ischaemia but not 30min
• Hypoxia results from
1. Inadequate amount of O2 in air
2. Respiratory disease
3. Ischaemia (decreased blood flow due to vasoconstriction or obstruction)
4. Anaemia
5. Oedema
6. Inability of cells to utilise O2 or
7. Hypermetabolic states with increased O2 consumption
Mechanism of cell death
• Pure hypoxia affects all cells of the body
• Ischemia is specifically to do with poor O2 delivery to tissue due to vasoconstriction
or obstruction – e.g. thromboembolism, atheromas
• Results in specific tissue damage
• Poor removal of anaerobic waste products (lactic acid)
• Hypoxia causes power failure
• Cell switches from aerobic to anaerobic metabolism, and it depletes it glycogen
stores to maintain vital cell function
• Cellular pH falls as lactic acid builds up
• Drop in pH can cause adverse effects on normal biochemical reactions and intracellular
structures
• Low pH can also affect membrane potentials and alter the structure of chromatin
Effects of ATP Depletion
• Reduced ATP can cause acute
swelling of cells
• Failure of the energy dependent
Na+/K+ ATPase exchanger, which
pumps out Na in exchange of K+
results in accumulation of Na+
and water inside the cell
• This affects the ER, increases
membrane permeability and
decreased mitochondrial function
Cell Death/ Reversible Cell Damage
• Cell injury may result in sub lethal damage or death
• Reversible cell damage can occur through cell swelling (depleted ATP)
• Or fat accumulation within cells, because normal fat metabolism pathways
are impaired. In obese patients fatty infiltrates usually occur in the liver and
heart
• Death occurs when
• Damaged cells are removed via apoptosis
• Necrosis is when the damage is severe
Major Mechanisms of Cellular Injury