Normal and Adapted Cell,

Cell injury and Death,

Inflammation and Repair.
PCL 311: 2018-2021
1. NORMAL CELL AND ADAPTED CELL
CELL ADAPTATION
Cell adaptations are reversible changes in number, size, phenotype, metabolic activity or
functions of a cell- not same as cell injury.
Physiologic- hormonal/ endogenous chemical mediators (breast development at
puberty) or
Pathologic- response to stress- modulation of activity to escape injury
Types;
hypertrophy, hyperplasia, atrophy, metaplasia
CELL ADAPTATION: Hypertrophy
Mechanism example
Mechanical triggers stretch
Trophic triggers activation of alpha-adrenergic
receptors

Stimuli- signal transduction pathways- induction of genes- stimulation of cellular protein

synthesis, growth factors and structural proteins- ↑myofilaments and proteins per cell hence
improved performance.
Possible switch in contractile protein from α-myosin heavy chain to β-myosin heavy chain
which has better ergonomical contractions
Adaptations are not perfectly elastic
CELL ADAPTATION: Hypertrophy
An increase in size of cells (due to increase structural proteins and organelles) resulting in
increase in the size of the organ.
Cells have limited ability to divide.
Physiologic- enlargement of striated skeletal and heart muscles in adults due to exercise, or
Pathologic- enlargement of cardiac muscles due to hypertension or aortic valve disease
CELL ADAPTATION: Hyperplasia
An increase in cell number. May occur with hypertrophy (e.g. gravid uterus)
and due to similar stimuli.
Cells must be able to divide and regulate replication.
Type Differential Example
Physiologic Hyperplasia Hormonal hyperplasia- hormonal Proliferation of glandular epithelium
stimuli of the female breast at
puberty/pregnancy
Compensatory hyperplasia- removal/ Mitotic activity after liver resection
disease leads to activation of leading to restoration of liver mass
polypeptide growth factors
Pathologic Hyperplasia Excessive hormonal or growth factor Endometrial hyperplasia resulting
stimulation in a disease state from imbalance between estrogen
and progesterone- abnormal
menstrual bleeding.
CELL ADAPTATION: Atrophy
Shrinkage in the size of the cell by the loss of cell substance
Functions may diminish but cells are not dead
Due to decreased workload, loss of innervation, diminished blood supply, inadequate
nutrition, loss of endocrine stimulation (menopause)and aging (senile atrophy)

Mechanism: decreased protein synthesis (↓metabolic activity) and increased protein

degradation (ubiquitin-proteasome pathway) e.g. cancer cachexia

Atrophy is accompanied by autophagy- starved cells eating its components in an attempt to

find nutrients and survive.
CELL ADAPTATION: Metaplasia
Reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by
another adult cell type.
Genetic reprogramming of stem cells rather than modification of already differentiated cells.
Respiratory epithelium of habitual smokers’ normal columnar cells are replaced by squamous
epithelium- loss of mucus secretion and ciliary clearance of particulate matter
Influences that induce metaplastic transformations if persistent may increase risk for
malignant transformation of epithelium.
Note gastric epithelium, in chronic gastric reflux, changes from squamous to columnar
SELF ASSESSMENT
Write short notes on the following, defining terms and differentiating with examples between physiologic and pathologic types of
each adaptation;
◦ Hypertrophy
◦ Hyperplasia
◦ metaplasia

In chronic gastric reflux, the gastric epithelium is transformed/ adapts, which of the following is true of the adaptation
A. It is an irreversible change where adult cell types are replaced by a different cell type
B. There is a genetic reprogramming of stem cells without modification of adult differentiated cells
C. The adult cells are modified
D. All of the above
E. A and C only

At puberty, glandular epithelium of the female breast undergoes

A. Hormonal hyperplasia
B. Compensatory hyperplasia
C. Hormonal hypertrophy
D. All of the above
E. A and C only
2. CELL INJURY AND CELL DEATH
Cell injury occurs when cells are stressed so severely that they are no longer able to adapt/
exposed to inherently damaging agents/ suffer from intrinsic abnormalities.
Reversible cell injury- functional and morphological changes are reversible if damaging
stimulus is removed.
Cell death occurs when injury becomes irreversible and can be necrosis or apoptosis- both
differ in morphology, mechanisms, and roles in disease and physiology.
2. CELL INJURY AND CELL DEATH: Causes
2. CELL INJURY AND CELL DEATH:
Morphologic alterations in injured cells
Reversible cell injury: cell swelling, fatty change, plasma membrane blebbing and loss of
microvilli, mitochondrial swelling, dilation of the endoplasmic reticulum and eosinophilia.
Necrosis: increased eosinophilia; nuclear shrinkage, fragmentation, and dissolution;
breakdown of plasma membrane and organellar membranes; myelin figures, leakage and
enzymatic digestion of cellular contents.
Apoptosis: nuclear chromatin condensation; formation of apoptotic bodies (fragments of
nuclei and cytoplasm)
2. CELL INJURY AND CELL DEATH:
Differentiating Necrosis and Apoptosis
FEATURE NECROSIS APOPTOSIS
CELLSIZE Enlarged (swelling) Reduced (shrinkage)
NUCLEUS Pyknosis– karyorrhexis-- Fragmentation into nucleosome
karyolysis size fragments
PLASMA MEMBRANE Disrupted Intact; altered structure,
especially orientation of lipids
CELLULAR CONTENT Enzymatic digestion; may leak Intact; may be released in
out of cell apoptotic bodies
ADJACENT INFLAMMATION Frequent No
PHYSIOLOGIC OR PATHOLOGIC Pathologic Often physiologic means of
ROLE eliminating unwanted cells, may
be pathologic after some cell
injury/DNA damage
2. CELL INJURY AND CELL DEATH:
Mechanism of Injury
2. CELL INJURY AND CELL DEATH:
Reversible and irreversible injury
2. CELL INJURY AND CELL DEATH:
Apoptosis
A Regulated mechanism of cell death that serves to eliminate unwanted and irreparably
damaged cells, with the least possible host reaction
Characterized by: enzymatic degradation of proteins and DNA, initiated by caspases; and
recognition and removal of dead cells by phagocytes

Initiated by two major pathways:

Mitochondrial (intrinsic) pathway is triggered by loss of survival signals, DNA damage and
accumulation of misfolded proteins (ER stress); associated with leakage of pro-apoptotic
proteins from mitochondrial membrane into the cytoplasm, where they trigger caspase
activation; inhibited by anti-apoptotic members of the Bcl family, which are induced by
survival signals including growth factors.
Death receptor (extrinsic) pathway is responsible for elimination of self-reactive lymphocytes
and damage by cytotoxic T lymphocytes; is initiated by engagement of death receptors
(members of the TNF receptor family) by ligands on adjacent cells
Self Assessment
List the mechanisms of Cell injury and cell death giving a brief description of each
Describe
◦ Ischemic and Hypoxic injury
◦ Ischemia-Reperfusion Injury
◦ Chemical Injury

What are the causes of Apoptosis in physiologic and pathologic conditions?

3. INFLAMMATION AND REPAIR- Signs
Rubor: redness due to increased blood flow and vasodilation
Calor: heat due to increase blood flow
Tumor: swelling from inflammatory edema
Dolor: pain from swelling and presence of inflammatory mediators
Function laesa: loss of function due to main and structural necrosis
3. INFLAMMATION AND REPAIR- Acute
Inflammation
A series of reactions of vascularized tissue to injury
Defends against foreign substances, dispose of dying or dead tissue, immobilize injured area or
compartmentalize injured area
Depends on severity of injury, immune status and temperature
3. INFLAMMATION AND REPAIR- Acute
Inflammation
EVENTS PARTICIPATING UNITS
NEUROLOGIC EVENT Initial vasoconstriction (transitory and reflexive) and
Gradual vasodilatation (relaxation of reflexive spasm
and causes bleeding to start)

HEMODYNAMIC EVENT Vasodilatation, slowing of blood flow, margination of

leukocytes, hemostasis and permeability changes

CELLULAR EVENTS Circulating leukocytes - marginated cells, basophils

(release anticoagulants), neutrophils (phagocytes),
monocytes and macrophages (arrive later to clean up)

CHEMICAL EVENTS Histamines, bradykinins, prostaglandins etc.

3. INFLAMMATION AND REPAIR- Acute
Inflammation
Immediate vasoconstriction– 1hour gradual vasodilation, hemostasis, mast cell degranulation,
margination of WBC, Large scale neutrophil response– later Hemoconcentration from edema,
ischemia, interaction with chemical mediators, emigration of larger WBCs, initiation of
complement system
Abscess, ulcers, cellulitis, pseudomembranous inflammation
3. INFLAMMATION AND REPAIR- Chronic
Inflammation
Recurrent inflammation prior to completion of repair or resolution
Cellular aspect:
Macrophages predominate, features monocytes, giant cells, fibroblasts and lymphocytes
CD8+ T-killer and CD4+ delayed hypersensitivity
Leads to hypertrophic scarring (build up of type I collagen in chronic inflammation/healing)
3. INFLAMMATION AND REPAIR- Chronic
Inflammation
Granulomatous inflammation- a granuloma is an abnormal structure built from at least two
activated macrophages adhering to one another-may be called epithelioid cells
Granulomas may be formed with caseation (typical in fungal infections, TB), suppuration (pus,
typical in infections that involve the lymph nodes- brucellosis, plague), around foreign bodies
(splinters, sutures, mucus plugs in cystic fibrosis) etc.
3. INFLAMMATION AND REPAIR-
Regeneration and Repair
Inflammation resolves when nonstructural cells are lost after inflammation/ damaged cells
have been regenerated or repaired by fibrous tissue
Labile cells/ continuous replicators e.g. skin, gut, hemopoietic cells
Stable cells have little proliferation without injury, but can divide rapidly if necessary eg liver,
renal parenchymal tissue
Permanent cells – healed by scarring eg brain, heart
3. INFLAMMATION AND REPAIR-
Regeneration and Repair
Tissue repair
1.Fibroplasia/ fibrous repair: formation of granulation tissue, infiltration of fibroblasts, collagen
laid down in random pattern (can be manipulated artificially)
2.Maturation and remodeling: scar matures, scar remodels (due to stress)- usually is more
fragile than tissue it replaces.
3. INFLAMMATION AND REPAIR-
Regeneration and Repair
Surgical wounds
1. healing by primary intention- wound has neatly apposed edges, no big scar is left
2. healing by secondary intention- granulation tissue is formed from bottom up since edges are
not apposed, big scar.
Factors responsible for wound healing: growth factors eg platelet derived growth factor,
epidermal growth factor, fibroblast growth factor, transforming growth factor, TNF/Cachectin
etc.
Self Assessment
INSTRUCTION: Choose the option that best suits the statement and the explanation after it.
A. The statement is true: the explanation is true and explains the statement
B. The statement is true: the explanation is true, but does not explain the statement
C. The statement is false: the explanation is a true statement.
D. The statement is false: the explanation is false
E. The options do not apply

Rubor is redness: and it is due to swelling and presence of inflammatory mediators.

Cellulitis is an acute inflammation state: the inflammatory process includes immediate vasoconstriction resulting from hemostasis, margination of
white blood cells, and later hemoconcentration resulting from edema, ischemia and interaction with chemical mediators.

Chronic inflammation usually heals without any scarring involved: this is due to build up of type I collagen in chronic inflammatory conditions

Granulomas may be formed with caseation in Tuberculosis patients: this is usually due to the mycobacterium infested cells dying to leave a cheese
like structure

Inflammation does not resolve: this typically occurs if no cells are lost or if damaged cells have been regenerated or repaired by fibrous tissue

Labile cells and stable cells heal by proliferation, while permanent cells heal by scarring: this observed difference is due to dissimilar abilities to detect
divine signals
Anti-inflammatory
drugs: NSAIDS and SAIDS
PCL311: 2020/2021
 Plan of lecture:
 Non steroidal Anti-inflammatory agents (NSAIDs)
 Non-selective NSAIDs
 COX2 Selective NSAIDs

 Steroidal Anti-inflammatory agents

Inflammation

Inflammation is a complex protective response of the organism to injury caused by damaging agents.

It is aimed at inactivation or removal of these agents and promoting healing.

The traditional names for signs of inflammation come from Latin:

Dolor (pain)

Calor (heat)

Rubor (redness)

Tumor (swelling)

Functio laesa (loss of function)

Mediators of inflammation
Prostaglandins Bradykinin Serotonin Histamine

Platelet Tumor
Interleukins-2 Gamma-
activating Necrosis
– 6, 10, 12,13 Interferon
factor Factor

Transforming
Lymphotoxin
Growth Factor
The role of some prostaglandins in the body
PGE 2 – vasodilation, bronchodilation, inhibition of gastric
acid secretion, stimulation of gastric mucus secretion,
sensitization of pain receptors to chemical and mechanical
stimuli, promotion of anterior pituitary hormones release;
PGF2α - uterus contraction, bronchoconstriction, decrease
in intraocular tension;
TXA2 (thromboxane), produced by platelets, - induction of
platelet aggregation, vasoconstriction;
PGI 2 - inhibition of platelet aggregation, potent
vasodilation;
Cyclo-Oxygenases (COX)

Exists in the tissue as constitutive isoform (COX-1).

At site of inflammation, cytokines stim the induction of the 2nd isoform (COX-2).

Inhibition of COX-2 is thought to be due to the anti-inflammatory actions of NSAIDs.

Inhibition of COX-1 is responsible for their GIT toxicity.

Most currently used NSAIDs are somewhat selective for COX-1, but selective COX-2 inhibitors are available.
 NSAIDs – nonsteroidal
anti-inflammatory drugs
1. Nonsteroidal anti-inflammatory
drugs (NSAIDs)
2. Pyrazolone
1. Salicylates e.g.
Nonselective COX derivatives e.g. 3. Indole derivatives
Acetylsalicylic acid
inhibitors: Phenylbutazone, e.g. Indomethacin
(Aspirin), Salicylamide
Metamizol (Analginum)

4. Propionic acid 5. Antranilic acid 6. Aryl – acetic acid

7. Oxicam derivatives
derivatives e.g. derivatives e.g. derivatives e.g.
e.g. Piroxicam
Naproxen Mephenamic acid Diclophenac sodium

8. Dihydropyrrolizine
carboxylic acid
derivative e.g. Ketorolac
 Selective COX inhibitors
Preferential COX-2 inhibitors:

Nimesulide
Meloxicam
Nabumeton
Selective COX-2 inhibitors:

Celecoxib
Parecoxib
Rofecoxib
NB!!!These drugs cause little gastric mucosa damage, they do not inhibit platelet
aggregation!!!
 Mechanism of action of NSAIDs
(Non-Steroidal Anti-Inflammatory Drugs)

• Act by inhibiting CycloOXygenases (COX) => no PG production

– COX-1: Constitutively expressed => house-keeping function
– COX-2: Induced by pro-inflammatory factors (TNFα, IL-1)
– COX-3: Just recently discovered
• PGs do not cause pain, but sensitize nocireceptors to stimulation (e.g. by 5-HT, Bradykinine,
capsaicin, …)
• IL-1 release from activated macrophages (bacteria, etc.) induces COX-2 in the brain =>PG E
produced => affects thermoregulation => fever=> NSAIDs have anti-pyretic effects
• Classical NSAIDs: inhibit both COX-1 and COX-2 (inhibition is reversible, with the exception of
Aspirin) => housekeeping PGs reduced => side effects (gastrointestinal, bronchospasms,…)
• 2nd generation NSAIDs: COX-2 specific => only the inflammatory response is inhibited => fewer
side effects.
Mechanism of anti-inflammatory drug action
Mechanism of anti-inflammatory drugs’
action
Pharmacological effects of NSAIDs
Anti-inflammatory
Analgesic
Antipyretic
Antiplatelet (Aspirin)
Closure of ductus arteriosus in newborn
Clinical uses of NSAIDs

3. Arthritises:
1. Pain: headache,
rheumatiod arthritis,
toothache, myalgia, 2. Fever;
osteoarthritis, gout,
backpain;
ankylosing spondylitis;

5. Unclosure of ductus 6. Prevention of MI,

4. Dismenorrhoea
arteriosus (especially stroke, and
(especially ibuprofen);
aspirin); reinfarction (aspirin);
Side effects of NSAIDs

1. GIT disturbances:
2. CNS disturbances:
epigastric pain, nausea, 3. Blood: Leukopenia,
dizziness, mental confusion, 4. Homeostasis: Water and
gastric peptic ulcer agranulocytosis
hallucination and psychosis, sodium retention, edema
(especially aspirin), (indomethacin,
depression (especially (phenylbutzone);
gastrointestinal bleeding phenylbutzone, metamizol);
indomethacin);
(especially indomethacin);

7. Bones: Disorders of 8. Liver: Increase in

6. Reye’s syndrom,
5. Hypersensitivity reactions cartilages and subchondral transaminase levels, liver
bronchospasm (aspirin)
tissue toxicity

9. Cardiovascular system:
10. Kidney: nephritic
arterial hypertension, 11. Asthmatic exercebation,
syndrome, acute kidney
cardiac insufficiency, polyps if the nose, skin rash
injury, kidney failure
stenocardia
 Contraindications
A) Pregnancy
B) Haemophilic patients
C) Hypersensitivity reactions
D) Viral infections mainly in children
E) Peptic ulcers
Drugs interaction
Potentiates the gastric irritant effect of alcohol
Potentiates the hypoglycaemic effects of oral hypoglycaemic drugs
The Salicylates - ASPIRIN
Duration of action ~ 4 hr.
Orally taken.
Weak acid (pKa ~ 3.5); so, non-ionized in stomach  easily absorbed.
Hydrolyzed by esterases in tissues and blood to salicylate (active) and acetic acid.
Most salicylate is converted in liver to water soluble conjugates that are rapidly excreted by
kidneys.
ASPIRIN - Therapeutic Uses
Antipyretic, analgesic.
Anti-inflammatory: rheumatic fever, rheumatoid arthritis (joint dis), other rheumatological
diseases. High dose needed (5-8 g/day).
But many pts cannot tolerate these doses (GIT); so, proprionic acid derivatives, ibuprofen,
naproxen tried first.
Prophylaxis of diseases due to inhibition of platelet aggregation.
Pre-eclampsia and hypertension of pregnancy (excess TXA2).
Propionic acid derivatives
IBUPROFEN:
Pharmacokinetics
Rapidly absorbed after oral ingestion.
Half-life 1-2 hours
Highly bound to plasma proteins
Excreted through kidney as metabolites
IBUPROFEN
The same mechanism & pharmacological actions of aspirin Except that it is reversible inhibitor
for COX enzymes
More potent as antiinflammatory than aspirin!!!
Clinical Uses:
A) Analgesic
B) Antipyretic
C) Anti-inflammatory
D)Acute gouty arthritis
E) Patent ductus arteriosus
Preparations of Ibuprofen
Oral preparations- tablets and capsules (200mg, 400mg, 800mg), syrups (100mg/5ml, 200mg/5ml).
Topical cream/ oral gels (e.g. A liquid gel for rapid relief of postsurgical dental pain) /topical gels/
ointments for osteoarthritis.
Intravenous route as In patent ductus arteriosus
Adverse Drug Effects
1.Gastric upset (less frequent than aspirin).
2.Fluid retention
3.Hypersensetivity reactions
4.Ocular disturbances
5.Rare hematologic effects (agranulocytosis & aplastic anaemia).
Contraindications
1. Peptic ulcer
2. Allergic patients to aspirin
3. Kidney impairment
4.Liver diseases
5.Pregnancy
6.Haemophilic patients
The concomitant administration of ibuprofen antagonizes the irrevesible platelet inhibition of
ASPIRIN (limit cardioprotective effect of aspirin).
Piroxicam
Mechanism of actions:
A) Non-selective inhibitors to COX1 & COX2
B) Traps free radicals
C) Inhibits polymorphonuclear leukocytes migration
D) Inhibits lymphocyte function.
Pharmacokinetics:
Well absorbed orally/ Half- Life 45 hours/ Given once daily
Adverse Effects:
Less frequent gastric upset (20%)., Dizziness, Tinnitus, Headache, Allergy.
Acetic acid derivatives
DICLOFENAC
Mechanism of action
Non-selective inhibitor to COX1 & COX2.
More potent as anti-inflammatory than analgesic and antipyretics.
Clinical Uses
A) Inflammatory conditions B) Musculoskeletal pain
C) Dysmenorrhea D) Acute gouty arthritis
E) Fever G) A topical gel for solar keratoses
F) Locally to prevent or treat post ophthalmic inflammation
Adverse effects:
Gastric upset, Renal impairment, Elevation of serum aminotransferase and Salt & water
retention.
Preparations of Diclofenac:
Diclofenac with misoprostol decreases upper gastrointestinal ulceration but may cause
diarrhea.
Diclofenac with omeprazole to prevent recurrent bleeding.
1% opthalmic preparation for postoperative opthalmic inflammation.
A topical gel 3% for solar keratoses.
Rectal suppository as analgesic or for postoperative nausea
Selective COX2 Inhibitors
Advantages: (Only Celecoxib remains available in clinical use.)
1. Highly selective inhibitors to COX2 enzyme.
2. Potent anti-inflammatory.
3. Have analgesic & antipyretic properties.
4. Highly bound to plasma proteins.
5. Lower incidence of gastric upset.
6. No effect on platelet aggregation (COX1).
7. Renal toxicities (they are not recommended for patients with severe renal insufficiency).
8. High incidence of cardiovascular thrombotic events with some of them as ROFECOXIB (withdrawn).
9. They are recommended in postoperative patients undergoing bone repair.
10. Also, indicated in primary familial adenomatous polyposis, dysmenorrhea, acute gouty arthritis, acute
musculoskeletal pain, ankylosing spondylitis.
Selective COX2 Inhibitors: Celecoxib
Mechanism of Action:
The mechanism of action of celecoxib is due to selective inhibition of cyclooxygenase-2 (COX-2), which is
responsible for prostaglandin synthesis, an integral part of the pain and inflammation pathway. [3] This
pharmacologic activity gives celecoxib its analgesic, anti-inflammatory, and antipyretic effects.
Clinical uses:
It is used to treat the pain and inflammation in osteoarthritis, acute pain in adults, rheumatoid arthritis,
ankylosing spondylitis, painful menstruation, and juvenile rheumatoid arthritis.
PHK/PHD:
It is metabolised in the liver, elimination half-life may be prolonged from 8hours to 11-13 hours in liver
disease.
Celecoxib is mainly (97%) bound to serum albumin.
Side effects:
Gas or bloating, sore throat, cold symptoms, constipation, dizziness and dysgeusia.
 SAIDs – steroidal
anti-inflammatory drugs
 Steroidal anti-inflammatory drugs
These drugs are like cortisol. 3. Long-acting
1. Short-acting glucocorticoids Betamethasone
(natural) Dexamethasone
Hydrocortisone Paramethasone
Cortisone 4.Topically acting glucocorticoids
2. Intermediate-acting Beclomethasone
glucocorticoids dipropionate
Prednisone Budesonide
Prednisolone Fluocinolone acetonide
Methylprednisolone Fluocortolone
Triamcinolone
Properties of SAIDs- Anti-inflammatory & Salt-retention 1/2
Properties of SAIDs- Anti-inflammatory & Salt-retention 2/2
MECHANISM OF ACTION OF SAIDs
Steroids inhibit action of phospholipase A2 from converting phospholipids to arachidonic acids
in the pathway for making cyclo-oxygenases.
 Clinical uses of SAIDs
Adrenal insufficiency
Arthritis
Collagen diseases (systemic lupus erythematosus, scleroderma)
Bronchial asthma
Severe allergic reactions
Autoimmune diseases
Skin diseases
Ulcerative colitis, Crohn’s disease
Cerebral edema
Organ transplantation and skin allograft
Septic shock
 Main side effects of SAIDs
Susceptibility to infections
Delayed healing of wounds
Osteoporosis
Growth retardation in children (not at doses used for asthma)
Peptic ulceration
Cushing habitus
Hyperglycaemia
Muscular weakness
Psychiatric disorders
Withdrawal syndrome