Basic principles of cell injury and Adaptation

Mr.B.CHAKRAPANI M.pharm (pH.D) ASSISTANT PROFESSOR HOD-PHARMACOLOGY DEPARTMENT OF PHARMACOLOGY

BHARAT INSTITUTE OF TECHNOLOGY

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

CLINICAL/FUNCTIONAL
Rudolph Virchow 1821-1902 The Father of Modern Pathology

Basic principles of cell injury and Adaptation

ETIOLOGY of Cell Injury

GENETIC CAUSES
ACQUIRED CAUSES

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.

ACQUIRED CAUSES
1. 2. 3. 4. 5. 6. 7. HYPOXIA AND ISCHAEMIA PHYSICAL AGENTS CHEMICAL AGENTS AND DRUGS MICROBIAL AGENTS IMMUNOLOGIC AGENTS NUTRITIONAL DERANGEMENTS PHYCHOLOGICAL FACTORS

HYPOXIA AND ISCHAEMIA

THE 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 monoxide poisoning, cardio respiratory in sufficiency, and increased demand of tissues.

HYPOXIA AND ISCHAEMIA

Cells of different tissues essentially require oxygen to generate energy and perform metabolic functions.

Deficiency of oxygen or hypoxia results in failure to carry out these activates by the cells. Hypoxia is the most common cause of cell injury.

Direct Physical Action

Major problems are hemorrhage & ischemia

Ionizing Radiation
Ionizes H2O into H+ & OHOH- attaches to DNA & prevents cell reproduction

DNA mutations

Chemicals & Drugs

Chemical Poisons Strong acids & alkalies Environmental Pollutants Insecticides & Pesticides O2 at high conc. Hypertonic Glucose & Salt Social agents alcohol, narcotics Therapeutic Drugs

Toxic Molecular Injury

Dose related

CHEMICAL INJURY

Microbial Agents
Immunologic Agents Hypersensitivity Reaction Anaphylactic Reaction Autoimmune Diseases

Infection

Microbes
Toxins can interfere with protein synthesis or utilization of O2.

Nutritional Derangements
Defeciency of : Nutrients starvation Protein Calorie Marasmus , Kwashiorkar Minerals Anemia Trace Elements Excess of : Obesity Atherosclerosis Heart ds

Psychological Factors
Drug Addiction Alcoholism Smoking Liver Damage Bronchitis Peptic Ulcer

Causes, Pathogenesis and morphology of cell injury

morphology of reversible cell injury

REVERSIBLE = INJURY IRREVERSIBLE = DEATH

SOME INJURIES CAN LEAD TO DEATH IF PROLONGED and/or SEVERE enough

Reversible Cell Injury

Hypoxia / Ischemia of short duration Decreased cellular ATP. Reduced Intracellular pH. Damage to plasma membrane sodium pump. Reduced Protein synthesis. Functional consequences. Ultrastructural changes.

INJURY CAUSES (REVERSIBLE)

Hypoxia, (decreased o2)

Physical agents

Chemical agents
Infectious agents
Immunologic
Genetic Nutritional

INJURY MECHANISMS (REVERSIBLE)

Decreased ATP

Mitochondrial damage
Increased Intracellular calcium Increased Free radicals

Increased Cell membrane Permeability

Morphology of Reversible cell injury

Degeneration / Retrogressive changes. Cellular Swelling / Hydropic / vacoular degeneration. Fatty change. Hyaline change. Mucoid change.

Classification of morphologic forms of cell injury

MECHANISM OF CELL INJURY 1.Reversible cell injury

NOMENCLATURE Retrogressive changes (de generation) Cell death- necrosis. Apoptosis Sub cellular alterations Intracellular accumulation of lipid ,protein, carbohydrate. Gangrene, pathologic calcification.

2.Irreversible cell injury 3.Programmed cell death 4.Residual effects of cell injury.
5.Deranged cell metabolism 6.After-effects of necrosis

Cellular Swelling
Due to : Impaired regulation of Cellular volume Na. Na accumulation in cell Cloudy Swelling Inflow of water Gross appearance Cellular swelling Hydropic change Accumulation of water Vacoular Cytoplasmic vacoulation

Cellular Swelling
Influx 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 Swelling

Dilatation of ER

Detachment of polysomes Mitochondrial swelling Blebs on plasma membrane Loss of fibrillarity of nucleolus

Fatty Change
Steatosis / Fatty Metamorphosis Intracellular accumulation of neutral fat in parenchymal cell Common in Liver

Hyaline Change
Hyaline = glassy
Glassy homogenous Eosinophilic appearance

Hyaline Change
INTRACELLULAR EPITHELIAL CELLS Hyaline droplets Zenkers degeneration Mallorys Hyaline Hyaline Inclusions
EXTRACELLULAR CONNECTIVE TISSUE Leiomyomas

Old scar
Hyaline Arteriosclerosis c/c GN

Russells bodies

Corpora amylacea

Mucoid Change
Connective tissueMucin Mucoid / Myxoid degeneration in tumours Dissecting aortic aneurysm EPITHELIAL MUCIN marfans syndrome Catarrh Myxomatous change in Mucocele dermis of myxodema

Proteins+ Mucopolysaccharide

Cystic fibrosis Mucin secreting tumours

Reversible & irreversible injury

MORPHOLOGY OF IRREVERSIBLE CELL INJURY(CELL DEATH)

Necrosis vs. Apoptosis

All disease occurs because of cell injury

Either because of the injury itself or the repair process that follows

NECROSIS

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.

Apoptosis
Pathologic Eliminates cells that are genetically altered or injured DNA damage Cell injury in certain infections viruses

Apoptosis
Examples Growth factor deprivation Hormone-sensitive cells deprived of the hormone Lymphocytes not stimulated by antigens Neurons deprived of nerve growth factor

Mitochondrial dysfunction

Ca2+ in cell injury

Stages in cellular response to stress and injurious stimuli

CONSEQUENCES OF ATP DEPLETION

Ischemic cell injury

Necrosis and apoptosis

Cell reaction to stimuli

CELLULAR ADAPTATIONS

Atrophy
Shrinkage in the size of the cell by loss of cell substance . Tissue or organ size diminishes in size. Function diminishes not death.

Cellular adaptations
Atrophy Hypertrophy

Metaplasia
Dysplasia Cellular aging

A-TROPHY
DE-CREASE IN SIZE OF CELLS
SHRINKAGE IN CELL SIZE DUE TO LOSS OF CELL SUBSTANCE

atrophy
Reduction of the number and size of parenchymal cells of an organ or its parts which was once normal is called atrophy. A. PHYSIOLOGIC ATROPHY: Atrophy is a normal process of aging in some tissues which could be due to loss of endocrine stimulation or arteriosclerosis. Example: Atrophy of a brain, Atrophy of lymphoid tissue in lymph nodes, appendix and thymus.

atrophy
1. 2. 3. 4. 5. 6. 7. STAVATION ATROPHY ISCHAEMIC ATROPHY DISUSE ATROPHY NEUROPATHIC ATROPHY ENDOCRINE ATROPHY PRESSURE ATROPHY IDIOPATHIC ATROPHY

Atrophy
CAUSES Immobilization Loss of innervation Diminished blood supply Inadequate nutrition Loss of endocrine stimulation Aging Autophagy can occur Physiologic and pathologic

ATROPHY
Decreased Workload Denervation Decreased Blood flow Decreased Nutrition Aging (Involution) Pressure

Hypertrophy
Increase in the size of cells resulting in increase in the size of the organ. No new cells, just bigger cells. Occurs in cells that cannot divide. Physiologic weight lifter. Pathologic - cardiac enlargement hypertension, aortic valve stenosis. Cardiac failure adaptation to stress can lead to functionally significant cell injury.

HYPER-TROPHY
IN-CREASE IN SIZE OF CELLS

Hyperplasia
Increase in cell number. Occurs in cells capable of replication. Can occur with hypertrophy. Physiologic. Hormonal breast during puberty and pregnancy. Compensatory part of tissue is removed: kidney, liver.

Cellular Aging
Result of a progressive decline in the proliferative capacity and life span of cells and the effects of continuous exposure to exogenous 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
Decreased cellular replication All normal cells have a limited capacity for replication Reduced regenerative capacity of stem cells Accumulation of metabolic damage Cellular life span is a balance between damage from metabolic events and molecular response that repair the damage

Cell and Tissue Injury

Cellular function may be long lost before cell death occurs Example 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: LIGHT MICROSCOPY

APOPTOSIS MORPHOLOGY
DE-crease in cell size, i.e., shrinkage IN-crease in chromatin concentration, i.e., hyperchromasia, pyknosis karyorhexis karyolysis IN-crease in membrane blebs Phagocytosis

Principle Sites of Damage in Cell Injury

Mechanisms of Cell Injury I s c h e m i c

i n j u r y

Principle Sites of Damage in Cell Injury

Cell reaction to stimuli

Inflammatory & Immune Reactions

Due to cell injury & then in turn causes injury