ChapterChapter :1 :1

PrinciplesPrinciples ofof cellcell injuryinjury andand adaptationadaptation

Presented by: Prof.Mirza Anwar BaigPresented by: Prof.Mirza Anwar Baig

Anjuman-I-Islam's Kalsekar Technical CampusAnjuman-I-Islam's Kalsekar Technical CampusSchool of Pharmacy,New Pavel,Navi School of Pharmacy,New Pavel,Navi

Mumbai,MaharashtraMumbai,Maharashtra

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Contents:• Causes of cell injury

• Pathogenesis and morphology of cell injury.

• Cellular adaptation

• Cellular atrophy and hypertrophy.

CELL INJURY

• Cell injury results from a disruption of one or more of the cellular components that maintain cell viability.

• Defined as variety of stresses a cell encounters as a result of internal or external environmental changes.

• Cell injury is common to all pathologic processes.

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CELL INJURY

• Cellular adaptation

• Reversible or irrversible cell injury

• Subcellular changes and intracellular accumlation

Injury at one point induces a cascade of effects.

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Etiology:• Hypoxia and Ischamia:

• Physical agents

• Chemicals and drugs

• Microbial agents

• Immunologic agents

• Nutritional derangemtns

• Psychogenic diseases

• Iatrogenic causes

• Idiopathic diseases

HYPOXIC INJURY

Cerebral infarction Myocardial infarction

Renal atrophy 6

INFECTIOUS DISEASE

Primary HerpesCandidiasis

Tuberculosis Actinomycosis

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PHYSICAL INJURY

Thermal Burn Traumatic ulcer

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CHEMICAL/DRUG INJURY

Asprin Burn9

Pathogenesis of cell injury

• General principles of pathogenesis

1. Type, duration and severity of injurious agents

2. Type, status and adaptability of target cell

3. Underlying intracellular phenomena

eg. Mitochondrial damage, cell wall damage, free

radicals

4. Morphological consequences

eg. Ultrastrucal changes, swelling10

OUTCOMES OF CELL INJURY

REVERSIBLE CELL DEATH CELLADAPTATIONS

NORMAL CELL

CELL INJURY / CELL STRESS

ACUTE CHRONIC

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1.Pathogenesis of ischemic and hypoxic injury

Reversible cell injury:1. Decreased generation of cellular ATP2. Intracellualar lactic acidosis: Nuclear clumping3. Damage to plasma membrane pump

- ATP dependent Na /K pump, Ca pump4. Reduced protein synthesis- Dispersed ribosomes

Irreversible cell injury:1. Mitochondrial damage- ↑ca influx2. Activated phospholipase- membrane damage3. Intracellular proteases- cytoskeleton damage4. Activated endonucleases- nuclear damage

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1.1: Ischemia reperfusion injury and free radical mediated cell injury

3 different consequences:

1. from ischaemia to reversible injury2. from ischaemia to reperfusion injury3. from ischaemia to irreversible injury

Mechanism:1. Calcium overload: ↑lipid peroxidation of cell

membrane2. Generation of ROS:3. Subsequent inflammatory reactions neutrophils utilize oxygen and gives free radicals 13

2. Pathogenesis of chemical injury:• Direct cytotoxic effect

– Direct cytotoxic effect: Hgcl2 poisoning, Anticancer agents

Conversion to reactive toxic metabolitesmetabolites kills the cells eg, CCl4 affects liver

Acetaminophen poisoning

3. Pathogenesis of physical injury:Ionizing radiations.- cell membrane & DNA

damage

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Cellular adaptation:Classifcation:a)Atrophy and Hypertrophy (↑or ↓in size)

b)Hyperplesia (↑number of cells)

c)Metaplasia (change from one type to another

type) and dysplasia (changed phenotypic

differentiation)

a. Atrophy1.Physiologic atrophy: Brain,Gonads,2.Pathologic atrophy

a)Starvation atrophy

b)Ischaemic atrophy eg, atropic kidney

c)Disuse atrohy eg, atropy of pancreas

d)Neuropathic atrophy eg. Motor neuron disease

e)Endocrine atrophy eg, atropy of thyroid and adrenal

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ATROPHY & ISCHEMIA

Renal atrophy

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ATROPHY & AGING

Normal Brain Atrophic Brain

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b. Hypertrophy– Physiologic hypertrophy eg uterus in

pregnancy– Pathologic hypertrophy

• Hypertrophy of cardiac muscle

• Hypertrophy of smooth muscle– Cardiac achalasia

– Pyloric stenosis

– Intestinal strictures

– Muscular arteries in hypertension

• Hypertrophy of skeletal muscle

• Compensatory hypertrophy eg, nephrectomy of one side, removal of one adrenal gland

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HYPERTROPHY & INCREASED FUNCTIONAL DEMAND

A

A

A = Normal heart

B

B

B = Hypertensive heart

C

C

C = Dilated heart20

c. Hyperplasia:• Temporary Increase in the number of the parenchymal cells.• Resulting in enlargement of organ.• Often hypertrophy and hyperplasia occures simultaneously• Occures due to increased in mitosis of the resting cells.• Neoplasia causes change in the genetic composition of the

cells.

CAUSES:A. PHYSIOLOGICAL HYPERPLASIA:I) Hormonal hyperplasia eg: ↑in size of breast during pregnancy

and lactation. Pregnant uterusii) Compensatory hyperplasia: Eg: Regenration of liver cells after

hepatectomy,epidermis after skin abrasion.

B.PATHOLOGIC HYPERPLASIA:I) Endometrial hyperplasia in excess oestrogenii) In wound healing: proliferation of fibroblasts cellsiii) Formation of skin warts: papilloma viral infection

d. Metaplasia:• It is defined as a reversible change of one type of

epithelial or mesenchymal cells to another type of adult epithelium or mesenchymal cells.

• long time metaplasia may result in cancer.• Divided in 2 types:A. EPITHELIAL METAPLASIA:

1. Squamous metaplasia: Eg: In bronchus of chronic smokers Utreus of old age

2. Columnar metaplasia:Eg: Intestinal metaplasia in healed chronic gastric ulcer.

B. MESENCHYMAL METAPLASIA:1. Osseous metaplasia: Eg: arterial wall in old age2. Cartilaginous metaplasia: Eg; healing of fractures

e. Dysplasia:• Means 'disordered cellular development'.

• Often accompanied with metaplasia and hyperplasia.

• Often occurs in epithelial cells.

• Observed charactertics are

– Increased number of layers of epithelial cells

– Increased mitotic activity

– Disorderly arrangement of cells from basel layer to surface layer.

– Cellular and nuclear pleomorphism (variability in the size, shape and staining of cells and/or their nuclei.)

Morphology of Reversible cell injury

1.Hydropic change-swelling-kidney, liver,pancreas

2.Hyaline change- glass like

3.Mucoid change- mucus

4.Fatty change- fat accumlation eg fatty liver

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Morphology of Irreversible cell injury

a) Autolysis or self digestion

b) Necrosis

c) Apoptosis

d) Gangrene

e) Calcification

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CONCEPTS - CELL DEATH

• There is no singal biochemical event that equates with cell death.

• Necrosis = “cell murder”

• Apoptosis = “programmed cell death or cell suicide”

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NECROSIS•Morphologic types of necrosis

– Coagulative

– Liquifactive

– Caseous

– Enzymatic (fat)

• The type of necrosis is dependent upon patterns of enzymatic degradation of cells and extracellular matrix, the type of necrotic debris, and by bacterial products when present.

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Coagulative necrosis:

• Common type of necrosis• caused by irreversible focal injury,ischemia.• Foci are pale,firm and slightly swollen.• Hall mark is presence of tombstones.

Liquefaction necrosis:Caused due to ischaemic injury or bacterial infection.Eg: infarct brain.Affected area is soft containing necrotic debris.

Caseous necrosis:Found in foci of tuberclosis infection.have the features of coagulative and liquefaction necrosis.Appears like dry cheese,soft, granular and yellowish.

Fat necrosis:• Present at pancrease and breast.• Yellowish white firm deposits.• Fat cells have cloudy appearance and

surrounded by inflammatory reactions.• Calcium soaps are present in the cells.Fibrinoid necrosis:• Deposition of fibrin like material.• Present in immunological tissue injuries.• Arterioles of hypertension,peptic ulcers.• Appears like brightly eosinophillic in vessel

wall.

COAGULATIVE NECROSIS

• Cell outline• Pink cytoplasm

• Anucleated cells

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COAGULATIVE NECROSIS

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CASEOUS NECROSIS

Tuberculosis

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Apoptosis:In 2 process:A. Physiological process:

1. During development of embryo2. Cells of hormone dependent tissues eg: endometrial sheeding, regression of lactating breast.3. Involution of thymus gland in early age.

B. Pathological process:1. Cell death in tumour exposed to chemotherapeutic agents2. Cell death by cytotoxic T cells in graft rejection.3. Progressive depletion of CD4 cells in AIDS.4. Cell death in viral infection5. Pathological atropy6. Cell death after exposure of radiations, hypoxia etc7. Degenerative diseases of CNS eg: Alzheimers disease etc8. Heart diseases

MORPHOLOGY OF APOPTOSIS

Progressive cell shrinkageChromatin condensation

Plasma membrane blebbingApoptotic bodies

Phagocytosis - no inflammation 34

MECHANISMS OF APOPTOSIS

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