Cellular Adaptation, Immunity, & inflammation:

 Physiology: the branch of biology dealing with the functions and vital processes of living organisms
- Mechanical, physical & biochemical
 Pathology: the study of functional and structural abnormalities that are expressed as diseases of organs
and systems
 Pathophysiology: the study of the methods used by cells to respond to stress and disease
Cellular Adaptation= Cellular response to persistent stress that is not lethal (callus formation)- occurs in
response to:
1. Normal or physiologic conditions pregnancy (inc functional demand- weight gain+ CO)
2. Adverse or pathologic conditions HTN
3. Reversible cell injury irritation + asthma
Major adaptive responses:
- These changes occur in response to physiologic demands
A. Physiologic - an increase in tissue size due to a normal condition
- Increase in size of the uterus during pregnancy
- Increase in muscle in response to weight training

B. Pathologic - an increase in tissue size due to an abnormal condition

- Increase in the size of the thyroid from abnormal hormonal stimulation
- Increase in breast size in males from a pituitary adenoma (prolactin- tumor)

1. Atrophy – decrease or shrinkage in cellular size

- Cells reduce their functions in response to injury
Cause:
- Disuse-reduced functional demand  smaller size of a limb once the cast is removed
- Denervationmuscle damage caused by nerve damage (paralyzed)
- Ischemia
- Nutrient starvation Anorexia
- Interruption of endocrine signals  Pituitary dysfunction
- Persistent cell injury
- Aging
2. Hypertrophy – increase in the size of individual cells with a change in functional capacity
- Occurs as result of increased demands
- Subsides when the increased demand is removed but may not resolve completely
- Organ enlargement may occur
- Important for cells that are not able to undergo mitotic division
ex: differentiated muscle cells
3. Hyperplasia – increase in total number of cells resulting from an increased rate of cellular mitotic
division
Cause:
- Increase physiologic demand (ex: erythropoiesis in high altitudes)
- Hormonal stimulation (ex: estrogen increases stromal cells)
- Persistent cell injury (ex: calluses from chronic friction)
4. Metaplasia – conversion of one differentiated cell type to another
- Due to persistent injury
- Reversible when the injury or the offending agent is removed
- However, cancerous transformations can occurex: smoking tobacco:
 o Causes chronic irritation of the bronchial mucosa
o Ciliated columnar epithelial cells are converted to stratified squamous epithelial cells
5. Dysplasia – disorderly growth due to variation in size, shape and arrangement within the tissue
- Occurs often in hyperplastic squamous epithelium and intestinal mucosa
o Have potential to transform into cancerous cells (precancerous)
- If entire thickness of epithelium is involved, this is called “carcinoma in situ” (CIS)
o AKA preinvasive carcinoma
o Does NOT invade the basement membrane
o In time, can progress to invasive carcinoma (so basically if it cancer it goes through)

Irreversible Cell Injury = when an injury is too severe for adaptation or repair cell death occurs by either:
A. NECROSIS- caused by ischemia or toxic injury
a) Acute injury causes cells to swell, rupture, & spill their contents into extracellular space
INFLAMMATION
- 4 types of tissue necrosis (depends on type of tissue affected):
1. Coagulative- commonly caused by anoxia  solid tissue/ muscle
2. Liquefactive- caused by pyogenic bacteria  brain
3. Fat- from digestive enzymes following pancreatic injury adipose and pancreas
4. Caseous- from M. Tuberculosis or fungi lung
b) Cellular death in a large area of tissue caused by interruption of blood supply to a large area (death
and decay of tissue due to loss of blood supply) (surgical debridement + amputation)
- 3 types of GANGRENE necrosis:
1. Wet: liquefactive necrosis
o Internal organs- very SMELLY
o Often results from wounds, burns, traumatic injuries
o YES Bacterial growth & infection pus, swollen, warm, red
o Lot of tissue liquefaction
o Usually develops rapidly due to blockage of venous/arterial blood flow
2. Dry: coagulative necrosis
o Black wrinkly tissue with line of demarcation
o Usually develops in diabetics and those with autoimmune disorders
o Often in the hands or legs and feet
o NOT associated with infection
o Little tissue liquefaction
o Early stages: dull pain, painful to palpate, cold, dry, wrinkled
o Later stages: changes from brown to purple/blue to black
3. Gas: gas bubbles in damaged muscle tissue
o Anaerobic infection (clostridia)
o Can develop in muscles and organs (crepitus when gas bubbles pop)
B. APOPTOSIS- cell suicide response
- Programmed cell death
- Cells DO NOT rupture but are INGESTED by neighboring cells  NO INFLAMMATION
- Occurs by 2 pathways:
1. Extrinsic (environmental)- extracellular signaling among cells
2. Intrinsic (cellular)- internal monitoring

Causes of Tissue Injury

A. ENDOGENOUS (INTERNAL)
 1. Tissue Necrosis
o Ischemia + Anoxia
2. Immune Reactions
o Allergies + Autoimmune diseases + hypersensitivity rxns
B. EXOGENOUS (EXTERNAL)
1. Infection
2. Trauma (blunt or penetrating)
3. Physical agents
o Burns, frostbite, irradiation
4. Chemical Agents
o Acids/bases + environmental toxins
5. Foreign bodies
Mechanisms of Cell Injury
1. ISCHEMIA AND HYPOXIA
- Tissue HYPOXIA is most often caused by ISCHEMIA
~ Injury is due to lack of oxygen, buildup of toxic substances, and deprivation of nutrients for
glycolysis
- Some damage is reversible after reperfusion
- However, a REPERFUSION INJURY can result due to:
a. Calcium overload
b. Formation of free radicals
c. Inflammation
- Eventually all ischemic tissue becomes necrotic

- Restoration of the blood supply should minimize the damage, but new procedures ("clot busting"
drugs and angioplasty techniques) have demonstrated that the extent of injury often increased when
the blood supply was restored.

- This additional damage, reperfusion injury, MAY be due to the activity of free radicals.

ISCHEMIA  anaerobic REPERFUSION  aerobic  ROBUST ROS GENERATION + Ca2+ OVERLOAD  ACTIVATION OF
INFLAMMATORY CASCADES- SUBCELLULAR SIGNAL ACTIVATION APOPTOSIS CYTOKINE RELEASE  DEATH

2. Infectious & immunological

- Viruses, bacteria and prions can cause direct or indirect tissue injury
a. Direct Injury- can be caused by the production of enzymes, exotoxins, and endotoxins
~ clostridium perfringens- enzymes
~ clostridium botulinum- exotoxins
~ E. Coli 0157H7- endotoxins
b. Indirect Injury- can be caused by the body’s own immune response
3. Nutritional
- Injury may result from a specific deficiency or excess
a. Some are cell type specific
~Iron- RBC (anemia)
~vitamin D- bone
b. Others are general
~Vitamin b 12- required for folate metabolism and DNA synthesis
~Vitamin C- anti-oxidant and hydroxylation of collagen
4. Chemical
 - May cause Direct and Indirect injury:
a. Environmental Air pollutants, heavy metals
b. Drugs Tylenol, methotrexate, ilicit drugs, alcohol
c. Corrosives/Cleaners carbon tetrachloride
d. Toxic Gases carbon monoxide
5. Physical and Mechanical
a. Thermal hot and cold
b. Atmospheric pressure changes high or low (nitrogen bubbles in blood- scuba drive)
c. Electrical
d. Radiation
6. Radiation
a. Radiation damage (seconds)
b. Cellular response (minutes)
c. Cell function/rate (Hours)
d. Drives medical consequences (years)
7. Free Radicals
- A reaction where an atom loses an electron becomes unstableseeks to find another electron
- Caused by:
a. Inflammatory processes
b. Ischemic episodes
c. Toxic chemicals/ poisons
- Attack membrane structure, denature proteins, and cause DNA to rupture
a. Nitric oxide prevents platelet aggregation and adherence
- Implicated in diseases of the joints, heart, kidneys, and lungs
- Evidence shows they may play a role in the formation of mutations during chemical carcinogenesis
- DNA is not right anymore – so they are replicating the damage

Inflammation:
- Occurs when cells are injured
- Begins the healing process- isolates the area
- Can be ACUTE or CHRONIC
a. ACUTE- may be exaggerated or sustained resulting in tissue damage (septic arthritis/ pneumonia)
b. CHRONIC- may result in scarring and fibrosis loss of function
~basis of many degenerative diseases
- Has 3 purposes:
1. Neutralize and destroy the offending agent
2. Limit the spread of the offending agent
3. Preparation to repair damage tissue
- 5 cardinal (local) signs:
1. Redness (rubor)
2. Swelling (tumor)
3. Heat (calor)
4. Pain (dolor)
5. Loss of function (function laesa)
Inflammation Pathogenesis:
- Increased vascular permeability need capillaries to be leaky to allow WBC to go into tissue
- Recruitment and emigration of leukocytes
- Phagocytosis of offending agent and cellular debris
Inflammation- vascular permeability
 - Vasoconstriction of arterioles near injured site
- Chemical mediators released from injured tissues
a. Histamines, prostaglandins, and leukotrienes
- Vasodilation and increased permeability results from the contraction and “rounding up’ of the
endothelial cells
- Fluid is pushed out of the vascular space (vessels) into the interstitial space local swelling
- Overall blood flow is increased to the area CARDINAL SIGNS
Inflammation- Leukocytes
- Increased blood flow to the area brings in neutrophils= CHEMOTAXIS
- MARGINATION= when neutrophils stick to the endothelium lining of capillary wall
- DIAPEDESIS= allows neutrophils to move between cells and pass into the inflamed tissue
Inflammation- Phagocytosis
- Neutrophils and monocytes (tissue
macrophages) produce enzymes that digest the
proten structure
a. Specialize in collagen and cellular matrix
degradation
b. Occurs intracellularly or extracellularly
depending on size
- Neutrophils die at the site of inflammation
(that’s what pus is)
- Macrophages clean up the debris and prepare
the site for healing

Inflammation- Phagocytosis/Repair
- Macrophage-derived cytokines: TNF-alpha, IL-1 & IL-6
a. Brain raise body temp, induce sleep & suppress appetite
b. Conservation of heat occurs due to vasoconstriction & inc. heat from shivering “shaking chills”
c. Stimulate release of neutrophils from bone marrow
d. Skeletal muscle increase protein catabolism
e. Liver release acute phase reactants (C-reactive protein and serum amyloid A) CRP high=infection
f. Indirectly increases fibrinogen which causes RBCs to aggregate increases ESR (elevated
sedimentation rate)
Inflammatory Exudates
1. Purpose:
- Transports leukocytes and antibodies
- Dilutes toxins
- Transports nutrients involved in repair
2. Types:
- Serous- watery, low protein content (blister)
- Purulent- neutrophils, protein and tissue debris (pus)
- Hemorrhagic- contains large amount of blood- in lungs
Chronic inflammation:
1. Etiology:
- Prolonged injury
- Prolonged infection
- Specific types of infection
 - Antigens (immune rxns)
2. Lesions
- Less exudative than acute injuries
- Occurs with fibrous repairs, scarring- long time exposure
Transudates VS. Exudates (chronic inflammation)
A. TRANSUDATES
- Collection of fluid in tissues or a space
- Accumulation is due to INCREASE hydrostatic pressure (edema formation) or DECREASE osmotic
pressure (pull) in the vascular system
- Are watery
- Have a LOW PROTEIN CONTENT
- Not super localized
B. EXUDATES (worse like cancer)
- Result from HIGH osmotic pressure in tissues due to HIGH PROTEIN CONTENT
- Etiology:
a. Thin water (HF)
b. Lymphatic obstruction
c. Cloudy or protein rich fluid
- Are more localized
1. Serous- fluid filled with small amounts of protein – less degree of damage (blisters)
2. Fibrinous- large amounts of fibrinogen (scab)
3. Purulent (pus)- filled with live and dead leukocytes)
a. Suppurative inflammation- inflammation with high purulent exudate
b. Abscess- localized collection of pus
c. Empyema- pus present in a body cavity like in lungs
Chronic inflammation REPAIR:
1. Regeneration= replacement of the destroyed tissue by similar cells to those previously present
- Most desired outcome
- Ex. Fractured bone is replaced by bone- not all cells are capable of this like the heart or neurons
2. Fibrous connective tissue repair= tissue previously present is replaced by dense, tough fibrous tissue
(scar)
- Provides a strong bridge across the area
- Does NOT restore original function
Systemic (clinical) manifestations of inflammation:
1. Fever
2. Neutrophilia
3. Lethargy
4. Muscle catabolism (wasting)

SEPSIS= uncontrolled infection

- Life threatening complication of an infection – treated aggressively and quickly
- Is a continuum of physiologic states:
a. Infection, systemic inflammation, hypoperfusion (MAP), tissue injury and organ failure
- The body’s overwhelming response to an infection
a. Chemicals trigger widespread inflammation cascade of reactions that damages multiple organ
systems organ failure
- Most dangerous to elderly and those with weakened immune systems, (ICU, burns, invasive devices
- Risk factors:
a. Extremes of age
 b. Cancer
c. Immunodeficiency
d. Chronic organ failure
e. Genetic factors (polymorphisms)
f. Bacteremia

STAGES OF SEPSIS
1. Systemic inflammatory response syndrome (SIRS) - must have at least 2 of the following:
- Temp > 101F or <96.8F
- HR>90 BPM
- RR>20 breaths/min
- WBC>12,000 or <4,000 OR 10% bands
2. Sepsis
- SIRS + a culture of documented infection
3. Severe sepsis: sepsis + organ dysfunction
- Hypotension or hypoperfusion
- Abrupt change in mental status- (must rule out UTI in
elderly patients)
- Oliguria, lactic acidosis
4. Septic shock
- Hypotension (unresponsive to fluid replacement) +
hypoperfusion  in ICU by this point

Sepsis Pathophysiology:
- Infection causes proinflammatory mediators cause collateral tissue injury
- Anti-inflammatory mediators may increase risk for secondary infections
a. Balance between pro and anti -inflammatory mechanisms is lost (homeostasis)
- Blood flow to vital organs becomes impairs
- Clots can form
a. In organs= organ failure
b. In extremities= gangrene
Symptoms of Sepsis:
- S- shivering, fever, cold
- E- extreme pain or general discomfort
- P- Pale or discolored skin
- S- sleepy, difficult to rouse, confused
- I- “I feel like I might die”
- S- short of breath
Most likely infections to cause sepsis:
1. Pneumonia
2. Abdominal infection
3. UTI
4. Bacteremia
Common complications of sepsis:
- Disseminated intravascular coagulation (DIC)
- Acute respiratory distress syndrome (ARDS)
- Acute kidney injury
- Hemodynamic compromise
Sepsis Rx:
 - Cultures (before antibiotics)
- Volume resuscitation (crystalloids)
- Antimicrobial therapy
- Vasopressors (norepinephrine) to constrict pressure

Immunity

Innate immunity
1. External
- Skin- lysozymes to destroy bacteria
- Digestive tract- acidity in the stomach and bacteria in the colon
- Respiratory tract- alveolar macrophages
2. Internal
- Phagocytic cells- destroys bacteria and toxins
- Interferons- protect cells that have not been infected by
virus
- Natural killer cells- destroy cells infected with virus
- Mast cells- release histamine and mediators of inflammation
Immunity
A. Active immunity= produced by an individual after exposure
- Either produced by the individual or given directly to them
- Naturally and passively acquired
B. Passive immunity- preformed antibodies or T cells are
transferred from donor to recipient
- Does not involve the hosts immune response at all
- Naturally and passively acquired

Alterations in immune function

Immunologic disease
1. Immune deficiency disease- poor response to foreign agents
2. Hypersensitivity (allergic) rxns- too much response to antigens
- Hypersensitivity is a broader term than allergy
~ can include unknown etiologies
~ exaggerated responses may not be antigen-antibody mediated
Autoimmunity
- The classical interpretation of abnormal immune response that causes disease is not quite accurate
- Autoimmune responses are common & necessary to regulate the immune system
 - When these mechanisms are disrupted, uncontrolled production of autoantibodies or abnormal cell
to cell recognition leads to tissue injury Autoimmune disease
~ Is essentially a hypersensitivity rxn to the body’s own components (attack yourself)
~ Mediated by lymphocytes &/ or antibodies
- Identification of specific autoantibodies may help to diagnose autoimmune diseases, but it is also
necessary to show that the autoimmune reaction is directly related to the disease process
1. Hashimotos thyroiditis
2. Type 1 diabetes
3. Systemic lupus erythematosus (SLE)

Alloimmunity= when the immune system of one person produced an immunologic reaction against tissues of
another person- transfusion rxn

Alloimmunity: Graft versus Host Disease (GVHD)

- Transplant of allogenic (donor) bone marrow or human stem cells has resulted in cures for diseases
that previously proved fatal
- First the recipient bone marrow and immune system must be conditioned (ablated)
- Occurs when the donated bone marrow or stem cells view the recipient’s body as foreign and attack
the body  can’t go back DEAD

Hypersensitivity immune response

- Hypersensitivity immune responses= when an individual has been immunologically primed, further
contact with that antigen leads to secondary boosting of immune response to get a bigger response
- Hypersensitivity is an altered immune response to that antigen resulting in damage to the individual
a. Has a strong genetic component (peanut allergy)
4 types of hypersensitivity immune responses divided based on mechanisms (ACID MNEMONIC)
- The first three types involve immunoglobulins
- The 4th type involves t lymphocytes

1. Type 1= IgE mediated (immediate hypersensitivity)

a. Atopy = a group of diesases
I. Allergic rhinitis, conjuncitivitis
II. Allergic asthma
III. Atopic dermatitis
IV. Allergic gastroenteropathy
- Inherited tendency to antigen-specific IgE reactions to environmental or food (pollen, mold, mites)
b. Anaphylaxis= most severe form of Type I hypersensitivity rxn (immediate)
- Generalized release of mast cell mediators
systemic anaphylaxis characterized by:
I. Hypotension or sock
II. Bronchospasm
III. GI 7 uterine muscle contractions
IV. Urticaria or angioedema (cutaneous forms
like hives- common)
- Can be fatal
- Most COMMON CAUSES of anaphylaxis:
Drugs
I. Antibiotics (penicillin)
II. Radiocontrast agents
 III. Antineoplastic drugs
IV. Nonsteroidal anti-inflammatory drugs
Serum
Insect venoms
Latex
Foods
- IgE antibody activated and degranulates mast cells vasoactive chemicals (from mast cells or
basophilic leukocytes)
- Rxn occurs within minuteshours
- May involve
~skin (urticaria)
~eyes (conjunctivitis)
~nasopharynx (rhinitis, rhinorrhea)
~resp system (asthma)
~GI tract (gastroenteritis)
2. Type 2= antibody mediated (cytotoxic) hypersensitivity
- Mediated by IgM or IgG to cell bound antigens activation of the complement cascade
- Involves destruction of host cells by:
a. Agglutination and phagocytosis
b. Lysis of cell membrane
- RBCs are common targets
a. ABO transfusions (antibodies exist in the recipient)
b. Rh hemolytic disease of newborn
c. Immune hemolytic anemia
3. Type 3= immune complex mediated hypersensitivity
- Complement mediated rxn to precipitates of antigen and antibody
a. Antigen-antibody complexes lodge in vessel walls vasoactive substances 7 mast cells recruit
complement. PMN leukocytes are attracted too acute inflammatory rxn
Examples:
a. Serum sickness- uncommon, occurs after injection with an antitoxin from animal
b. Glomerulonephritis
c. SLE
4. Type 4= T cell mediated (delayed) hypersensitivity
- Mediated by T lymphocytes & macrophages
a. Antigen deposition cause activation of T cells cytokine release macrophage activation and
inflammation
- Peaks 24-48 hours delayed
- Caused by intradermal, epidermal and dermal antigens
a. Allergic contact dermatitis is most common
b. Poison ivy and oak (rhus species)
c. Nickel, formaldehyde

Disease States
1. SLE= systemic lupus erythematosus- a chronic inflammatory disease that is generally characterized bu
multiple relapses and remissions over decades and can affect virtually every organ system
- No two cases of SLE present in the same manner
- Clinical manifestations may develop suddenly or slowly, may be mild or severe and temporary or
permanent
- Considered an AUTOIMMUNE or COLLAGEN VASCULAR DISEASE
 a. Becomes symptomatic when the immune system attacks native tissues
- Butterfly rash
- Excessive helper T cell or defective suppressor T cell function induces clones of hyperactive B
lymphocytes to synthesize a variety of antibodies (AUTOANTIBODIES) against native tissues
- Since the immune system does not inherently attack native tissues, this phenomenon is known as loss
of immune self-tolerance
- Native tissues are apparently rendered foreign by exposure to various environmental agents (EBV)-
autoimmune diseases must have a trigger
- Autoantibodies have been identified against may nuclear and cytoplasmic components, including DNA
- These autoantibodies combine with antigens against which the antibodies were produced
(autoantigens) and antigen-antibody complexes (immune complexes) are formed in specific tissues
- May of the clinical manifestations of SLE result when immune complexes become trapped in tissues
- An intense inflammatory reaction develops to rid the body of the foreign immune complexes
a. TYPE 3 immune complex-mediated hypersensitivity immune reaction
- Autoantibodies have also been detected against various cell surface antigens (WBC, RBS, Plts)
- Immune complexes form on cell surfaces subsequent activation of critical proteins of the
complement system in response to immune-complex formation results in LYSIS
a. Type 2 complement mediated cytotoxic hypersensitivity reaction
- INFLAMMATION is the ultimate cause of tissue and organ injury in SLE
2. AIDS- acquired immunodeficiency syndrome- advanced, serious, state of clinical course following
infection with HIV 1 or 2
- AIDS is a SECONDARY AQUIRED chronic immunodeficiency characterized by:
a. Profound defect in cellular immunity
b. Low CD4 (helper) T Lymphocyte count (<200)
c. Reversal of normal CD4:CD8 lymphocyte ratio
d. AND 26 conditions that are common in advanced HIX disease but rarely occur in healthy people
- Transmission by sex, needles, perinatally
- Acute HIV infection may be present with:
a. Fatigue
b. Pharyngitis
c. Myalgias
d. Rash
e. Lymphadenopathy
- AIDS associated opportunistic infections: (die from complications)
a. Pneumonia
I. Pneumocystis jiroveci- most common organism
II. S. pneumoniae
III. H. influenza
IV. M. Tuberculosis
b. Oral candidiasis (thrush)
c. Hary leukoplakia
d. CNS:
I. Toxoplasmosis
II. AIDs dementia complex
e. PNS:
I. CMV (cytomegaly virus) – associated ascending polyradiculopathy
II. Retinitis
f. Cancer
I. Kaposi’s sarcoma
 - Lentivirus (animal retrovirus) exhibits LONG TERM Latency and aggressive cell injury – 10 yrs
- Results in fatal, slowly progressive diseases that include immunodeficiency, wasting syndromes, and
CNS degeneration
- HIV infects a limited number of cell types in the body (only those with CD4 receptors) including:
a. CD4 T lymphocytes *
b. Macrophages
c. Dendritic cells
d. NK cells
e. Microglia (immune system) in the CNS
Pathogenesis of HIV:
1. Attachment of HIV to the CD4 receptor
2. Un-coating and internalization of HIV.
3. RNA conversion to DNA via viral reverse transcriptase
4. Integration of viral DNA into host DNA via integrase
5. Transcription of the inserted viral DNA to produce messenger RNA (mRNA).
6. Translation of viral mRNA to create a viral polyprotein.
7. Cleavage of viral polyprotein
8. Assembly and release of new viral particles from the host cell
AIDS:
- The loss of CD4 cells in HIV result from
a. Autoimmune destruction
b. Direct viral infection/destruction
c. Fusion and formation into multinucleated giant cells
d. Toxicity of viral proteins to CD4 T lymphocytes & hematopoietic precursors
e. Apoptosis
AIDS clinical manifestations:
- Fever, fatigue
- Unexplained weight loss
- LAD
- Opportunistic infections
a) Pneumonia
b) Sinusitis
c) Candidiasis
d) Toxoplasmosis
e) Cryptococcal meningitis
f) Cytomegalovirus (CMV) retinitis
g) Neuropathy, polyarticular arthritis