ETIOLOGY of Cell Injury

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pathophysiology of pharm D II year

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Basic principles of cell injury and Adaptation:

Basic principles of cell injury and Adaptation BHARAT INSTITUTE OF TECHNOLOGY Mr.B.CHAKRAPANI M.pharm ( pH.D ) ASSISTANT PROFESSOR HOD-PHARMACOLOGY DEPARTMENT OF PHARMACOLOGY MANGALAPALLY,IBRAHIMPATNAM(M), R.R Dist .

CLINICAL/FUNCTIONAL:

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

Basic principles of cell injury and Adaptation:

Basic principles of cell injury and Adaptation

ETIOLOGY of Cell Injury:

ETIOLOGY of Cell Injury GENETIC CAUSES ACQUIRED CAUSES

GENETIC CAUSES :

GENETIC CAUSES THE GENETIC CAUSES OF VARIOUS DISEASES: Developmental defects. C ytogenetic defects: chromosomal abnormalities. S ingle gene defects: Mendelian disorders. M ultifactorial inheritance disorders. O ther pediatric diseases.

ACQUIRED CAUSES:

ACQUIRED CAUSES HYPOXIA AND ISCHAEMIA PHYSICAL AGENTS CHEMICAL AGENTS AND DRUGS MICROBIAL AGENTS IMMUNOLOGIC AGENTS NUTRITIONAL DERANGEMENTS PHYCHOLOGICAL FACTORS

HYPOXIA AND ISCHAEMIA:

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. H ow 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:

HYPOXIA AND ISCHAEMIA C ells of different tissues essentially require oxygen to generate energy and perform metabolic functions. D eficiency of oxygen or hypoxia results in failure to carry out these activates by the cells. H ypoxia is the most common cause of cell injury.

Direct Physical Action:

Direct Physical Action Major problems are hemorrhage & ischemia

Ionizing Radiation:

Ionizing Radiation Ionizes H 2 O into H + & OH - OH - attaches to DNA & prevents cell reproduction DNA mutations

Chemicals & Drugs:

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:

Toxic Molecular Injury Dose related

CHEMICAL INJURY:

CHEMICAL INJURY

Microbial Agents:

Microbial Agents Immunologic Agents • Hypersensitivity Reaction • Anaphylactic Reaction • Autoimmune Diseases Infection

Microbes:

Microbes Toxins can interfere with protein synthesis or utilization of O 2.

Nutritional Derangements:

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

Psychological Factors:

Psychological Factors Drug Addiction Alcoholism Smoking Liver Damage Bronchitis Peptic Ulcer

Causes, Pathogenesis and morphology of cell injury:

Causes, Pathogenesis and morphology of cell injury

morphology of reversible cell injury:

morphology of reversible cell injury

Slide 20:

REVERSIBLE = INJURY IRREVERSIBLE = DEATH SOME INJURIES CAN LEAD TO DEATH IF PROLONGED and/or SEVERE enough

Slide 22:

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

INJURY CAUSES (REVERSIBLE):

INJURY CAUSES (REVERSIBLE) Hypoxia, (decreased o2) Physical agents Chemical agents Infectious agents Immunologic Genetic Nutritional

INJURY MECHANISMS (REVERSIBLE):

INJURY MECHANISMS (REVERSIBLE) Decreased ATP Mitochondrial damage Increased Intracellular calcium Increased Free radicals Increased Cell membrane Permeability

Morphology of Reversible cell injury :

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:

Classification of morphologic forms of cell injury MECHANISM OF CELL INJURY 1.Reversible cell injury 2.Irreversible cell injury 3.Programmed cell death 4.Residual effects of cell injury. 5.Deranged cell metabolism 6.After-effects of necrosis NOMENCLATURE Retrogressive changes (de generation) Cell death- necrosis . Apoptosis Sub cellular alterations Intracellular accumulation of lipid ,protein, carbohydrate . Gangrene, pathologic calcification .

Cellular Swelling :

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

Cellular Swelling:

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 :

Ultra structural changes : Hydropic Swelling Dilatation of ER Detachment of polysomes Mitochondrial swelling Blebs on plasma membrane Loss of fibrillarity of nucleolus

Fatty Change:

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

Hyaline Change:

Hyaline Change Hyaline = glassy Glassy homogenous Eosinophilic appearance

Hyaline Change:

Hyaline Change INTRACELLULAR – EPITHELIAL CELLS Hyaline droplets Zenkers degeneration Mallory’s Hyaline Hyaline Inclusions Russell’s bodies EXTRACELLULAR – CONNECTIVE TISSUE Leiomyomas Old scar Hyaline Arteriosclerosis c/c GN Corpora amylacea

Mucoid Change:

Mucoid Change Connective tissueMucin Mucoid / Myxoid degeneration in tumours Dissecting aortic aneurysm – marfan’s syndrome Myxomatous change in dermis of myxodema Proteins+ Mucopolysaccharide EPITHELIAL MUCIN Catarrh Mucocele Cystic fibrosis Mucin secreting tumours

Reversible & irreversible injury:

Reversible & irreversible injury

MORPHOLOGY OF IRREVERSIBLE CELL INJURY(CELL DEATH):

MORPHOLOGY OF IRREVERSIBLE CELL INJURY(CELL DEATH)

Necrosis vs. Apoptosis:

Necrosis vs. Apoptosis

Slide 39:

All disease occurs because of cell injury Either because of the injury itself or the repair process that follows

NECROSIS:

NECROSIS

Apoptosis:

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:

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

Apoptosis:

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:

Mitochondrial dysfunction

Ca2+ in cell injury:

Ca2+ in cell injury

Stages in cellular response to stress and injurious stimuli:

Stages in cellular response to stress and injurious stimuli

CONSEQUENCES OF ATP DEPLETION:

CONSEQUENCES OF ATP DEPLETION

Ischemic cell injury:

Ischemic cell injury

Necrosis and apoptosis:

Necrosis and apoptosis

Cell reaction to stimuli:

Cell reaction to stimuli

CELLULAR ADAPTATIONS:

CELLULAR ADAPTATIONS

Atrophy:

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:

Cellular adaptations Atrophy Hypertrophy Metaplasia Dysplasia Cellular aging

A-TROPHY:

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

atrophy:

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:

atrophy STAVATION ATROPHY ISCHAEMIC ATROPHY DISUSE ATROPHY NEUROPATHIC ATROPHY ENDOCRINE ATROPHY PRESSURE ATROPHY IDIOPATHIC ATROPHY

Atrophy:

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

ATROPHY:

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

Hypertrophy:

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:

HYPER-TROPHY IN - CREASE IN SIZE OF CELLS

Hyperplasia:

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:

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:

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:

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:

DEATH: LIGHT MICROSCOPY

APOPTOSIS MORPHOLOGY:

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:

Principle Sites of Damage in Cell Injury

Slide 71:

Mechanisms of Cell Injury Ischemic injury

Principle Sites of Damage in Cell Injury:

Principle Sites of Damage in Cell Injury

Cell reaction to stimuli:

Cell reaction to stimuli

Inflammatory & Immune Reactions:

Inflammatory & Immune Reactions Due to cell injury & then in turn causes injury