ETIOLOGY of Cell Injury

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Basic principles of cell injury

and Adaptation

BHARAT INSTITUTE OF TECHNOLOGY

Mr.B.CHAKRAPANI M.pharm (pH.D)ASSISTANT PROFESSORHOD-PHARMACOLOGY

DEPARTMENT OF PHARMACOLOGY

MANGALAPALLY,IBRAHIMPATNAM(M), R.R Dist.


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CLINICAL/FUNCTIONAL

Rudolph Virchow

1821-1902

The Father of

Modern Pathology


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Basic principles of cell injury

and Adaptation


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ETIOLOGY of Cell Injury

GENETIC CAUSES

ACQUIRED CAUSES


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GENETIC CAUSES

THE GENETIC CAUSES OF VARIOUS

DISEASES:

1. Developmental defects.

2. Cytogenetic defects: chromosomal

abnormalities.

3. Single gene defects: Mendelian disorders.4. Multifactorial inheritance disorders.

5. Other pediatric diseases.


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ACQUIRED CAUSES

1. HYPOXIA AND ISCHAEMIA

2. PHYSICAL AGENTS

3. CHEMICAL AGENTS AND DRUGS4. MICROBIAL AGENTS

5. IMMUNOLOGIC AGENTS

6. NUTRITIONAL DERANGEMENTS7. PHYCHOLOGICAL FACTORS


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HYPOXIA AND ISCHAEMIATHE CAUSES OF HYPOXIA ARE AS UNDER:

The most common mechanism of hypoxic cell

injury is by reduced supply of blood to cells .i.e.

ischemia.

How ever , oxygen deprivation of tissues may

result from other causes as well e.g: In anemia ,

carbon monoxidepoisoning, cardio respiratoryin sufficiency, and increased demand of tissues.


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HYPOXIA AND ISCHAEMIA

Cells of different tissues essentially requireoxygen to generate energy and performmetabolic functions.

Deficiency of oxygen or hypoxia results infailure to carry out these activates by the cells.

Hypoxia is the most common cause of cellinjury.


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Direct Physical Action

Major problems are

hemorrhage & ischemia


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Ionizing Radiation

Ionizes H2O into H+ &

OH-

OH- attaches to DNA &

prevents cellreproduction

DNA mutations


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Chemicals & Drugs

Chemical Poisons

Strong acids & alkalies

Environmental Pollutants

Insecticides & Pesticides

O2 at high conc.

Hypertonic Glucose & Salt

Social agents alcohol, narcotics

Therapeutic Drugs


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ToxicMolecular Injury

Dose related


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CHEMICAL INJURY


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Microbial Agents

Immunologic Agents

Hypersensitivity Reaction

Anaphylactic Reaction Autoimmune Diseases

Infection


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Microbes

Toxins can interfere

with protein synthesis

or utilization of O2.


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Nutritional Derangements

Defeciency of:

Nutrientsstarvation

Protein CalorieMarasmus , Kwashiorkar

MineralsAnemia

Trace Elements Excess of :Obesity

Atherosclerosis

Heart ds


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Psychological Factors

Drug Addiction

Alcoholism

SmokingLiver Damage

Bronchitis

Peptic Ulcer


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Causes, Pathogenesis and

morphology of cell injury


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morphology of reversible

cell injury


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REVERSIBLE = INJURYIRREVERSIBLE = DEATH

SOME INJURIES CAN LEAD TO

DEATH IF PROLONGED and/or

SEVERE enough


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v y


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Hypoxia / Ischemia of short duration

Decreased cellular ATP.

Reduced Intracellular pH.

Damage to plasma membrane sodiumpump.

Reduced Protein synthesis.

Functional consequences.

Ultrastructural changes.

Reversible Cell Injury


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INJURY CAUSES (REVERSIBLE)

Hypoxia, (decreased o2)

Physical agents

Chemical agents

Infectious agents

Immunologic

Genetic

Nutritional


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INJURY MECHANISMS (REVERSIBLE)

Decreased ATP

Mitochondrial damage

Increased Intracellular calcium

Increased Free radicals

Increased Cell membrane Permeability


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Morphology of Reversible cell injury

Degeneration / Retrogressive changes.Cellular Swelling / Hydropic / vacoular

degeneration.

Fatty change.

Hyaline change.

Mucoid change.


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Classification of morphologic forms

of cell injury

MECHANISM OF CELL INJURY

1.Reversible cell injury

2.Irreversible cell injury3.Programmed cell death

4.Residual effects of cell injury.

5.Deranged cell metabolism

6.After-effects of necrosis

NOMENCLATURE

Retrogressive changes (degeneration)

Cell death- necrosis.Apoptosis

Sub cellular alterations

Intracellular accumulation oflipid ,protein, carbohydrate.

Gangrene, pathologiccalcification.


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Cloudy SwellingGross appearance

Hydropic change

Accumulation of water

Vacoular

Cytoplasmic vacoulation

Cellular Swelling

Due to :

Impaired regulation of

Cellular volume Na.

Na accumulation in cellInflow of water

Cellular swelling


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Cellular SwellingInflux of Na & extracellular water; escape of K.

cells swollen & microvasculature compressed.

Cellular Swelling.

Distended cisternae of ER small clear vacuoles. Vacoular Degeneration.

Ultrastructural changes : Hydropic Swelling.

Ultra structural changes : Hydropic


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Ultra structural changes : HydropicSwelling

Dilatation of ER

Detachment of polysomes

Mitochondrial swelling

Blebs on plasma membrane

Loss of fibrillarity of nucleolus


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Fatty Change

Steatosis / Fatty

Metamorphosis

Intracellular

accumulationof neutral fat in

parenchymal cell

Common in Liver


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HyalineChangeHyaline = glassy

Glassy homogenous

Eosinophilic appearance


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Hyaline Change

INTRACELLULAR

EPITHELIAL CELLS

Hyaline droplets

Zenkers degeneration

Mallorys Hyaline

Hyaline Inclusions

Russells bodies

EXTRACELLULAR

CONNECTIVE TISSUE

Leiomyomas

Old scar

Hyaline

Arteriosclerosis

c/c GN

Corpora amylacea


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Mucoid Change

Connective tissueMucin

Mucoid / Myxoid

degeneration in tumours

Dissecting aortic aneurysm

marfans syndrome

Myxomatous change in

dermis of myxodema

Proteins+

Mucopolysaccharide

EPITHELIAL MUCIN

Catarrh

Mucocele

Cystic fibrosisMucin secreting

tumours


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MORPHOLOGY OF IRREVERSIBLE CELL

INJURY(CELL DEATH)


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Necrosis vs. Apoptosis


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All disease occurs because

of cell injuryEither because of the injury

itself or the repair processthat follows


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NECROSIS


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Apoptosis

Cell destroys its own nuclear DNA and nuclear

and cytoplasmic proteins.

Plasma membrane remains intact.

Membrane altered inducing Phagocytosis but

no leakage.

No inflammation.


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Apoptosis

Pathologic

Eliminates cells that are genetically altered or

injured

DNA damage

Cell injury in certain infectionsviruses


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Apoptosis

Examples

Growth factor deprivation

Hormone-sensitive cells deprived of the

hormone

Lymphocytes not stimulated by antigens

Neurons deprived of nerve growth factor


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Mitochondrial dysfunction


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Mitochondrial dysfunction


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Ca2+ in cell injury

Stages in cellular response to


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Stages in cellular response to

stress and injurious stimuli


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CONSEQUENCES OF ATP DEPLETION

Ischemic cell injury


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Ischemic cell injury

Necrosis and apoptosis


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Necrosis and apoptosis


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Cell reaction to stimuli


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CELLULAR ADAPTATIONS

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Atrophy

Shrinkage in the size of the cell by loss of cellsubstance .

Tissue or organ size diminishes in size.

Function diminishesnot death.


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Cellular adaptations

Atrophy

Hypertrophy

Metaplasia

Dysplasia

Cellular aging

Y


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A-TROPHY

DE-CREASE IN SIZE OF CELLS

SHRINKAGE IN CELL SIZE DUE TO LOSS OF

CELL SUBSTANCE

atrophy


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atrophy

Reduction of the number and size of parenchymalcells of an organ or its parts which was oncenormal is called atrophy.

A. PHYSIOLOGIC ATROPHY: Atrophy is anormal process of aging in some tissues whichcould be due to loss of endocrine stimulation orarteriosclerosis.

Example: Atrophy of a brain, Atrophy oflymphoid tissue in lymph nodes, appendix andthymus.

atrophy


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atrophy1. STAVATION ATROPHY

2. ISCHAEMIC ATROPHY

3. DISUSE ATROPHY

4. NEUROPATHIC ATROPHY

5. ENDOCRINE ATROPHY

6. PRESSURE ATROPHY7. IDIOPATHIC ATROPHY

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Atrophy

CAUSESImmobilization

Loss of innervation

Diminished blood supplyInadequate nutrition

Loss of endocrine stimulation

AgingAutophagy can occur

Physiologic and pathologic

ATROPHY


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ATROPHYDecreased Workload

Denervation

Decreased Blood flowDecreased Nutrition

Aging (Involution)

Pressure

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Hypertrophy

Increase in the size of cells resulting in increase inthe size of the organ.

No new cells, just bigger cells.

Occurs in cells that cannot divide.Physiologicweight lifter.

Pathologic - cardiac enlargement hypertension,aortic valve stenosis.

Cardiac failure adaptation to stress can lead tofunctionally significant cell injury.

HYPER TROPHY


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HYPER-TROPHYIN-CREASE IN SIZE OF CELLS

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Hyperplasia

Increase in cell number.

Occurs in cells capable of replication.

Can occur with hypertrophy.

Physiologic.

Hormonalbreast during puberty andpregnancy.

Compensatorypart of tissue is removed:kidney, liver.

Cellular Aging


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Cellular Aging

Result of a progressive decline in theproliferative capacity and life span of cells andthe effects of continuous exposure toexogenous factors that cause accumulation of

cellular and molecular damage.Responsible mechanisms.DNA damage.Occurs during normal replication.

Defects in DNA repair mechanisms .DNA repair mechanisms can be

activated by caloric restriction.

Cellular Aging


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Cellular Aging

Decreased cellular replication

All normal cells have a limited capacity for

replication

Reduced regenerative capacity of stem cellsAccumulation of metabolic damage

Cellular life span is a balance between damage

from metabolic events and molecular responsethat repair the damage

Cell and Tissue Injury


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Cell and Tissue Injury

Cellular function may be long lost before cell death occursExample of myocardial cells.

Reversible injury:

Cellular swelling.Fatty change.Liver and heart.

Irreversible injury:Inability to reverse mitochondrial dysfunction.Profound disturbances in membrane function.

DEATH:


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DEATH:LIGHT MICROSCOPY

APOPTOSIS MORPHOLOGY


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APOPTOSISMORPHOLOGY

DE-crease in cell size, i.e., shrinkage

IN-crease in chromatin concentration, i.e.,hyperchromasia, pyknosis karyorhexis

karyolysis

IN-crease in membrane blebsPhagocytosis

Principle Sites of Damage in Cell


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PrincipleSites of Damage in Cell

Injury

Mechanisms of Cell Injury


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Principle Sites of Damage in Cell


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Injury


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Inflammatory & Immune


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Reactions

Due to cell injury &then in turn causes

injury


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ETIOLOGY of Cell Injury

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