Cell Injury I Cell Injury and Cell Death

Key Concepts • Normal cells have a fairly narrow range of function or steady

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Key Concepts (cont’d) • Cell injury can be reversible or irreversible • Reversibility depends

Cell Injury – General Mechanisms • Four very interrelated cell systems are particularly vulnerable

Cell Injury – General Mechanisms • • Loss of calcium homeostasis Defects in membrane

Causes of Cell Injury and Necrosis • Hypoxia – Ischemia – Hypoxemia – Loss

Reversible Injury • Mitochondrial oxidative phosphorylation is disrupted first Decreased ATP – Decreased Na/K

Irreversible Injury • Mitochondrial swelling with formation of large amorphous densities in matrix •

Cell Injury • Membrane damage and loss of calcium homeostasis are most crucial •

Clinical Correlation • Injured membranes are leaky • Enzymes and other proteins that escape

Free Radicals • Free radicals have an unpaired electron in their outer orbit •

Examples of Free Radical Injury • • Chemical (e. g. , CCl 4, acetaminophen)

Mechanism of Free Radical Injury • Lipid peroxidation damage to cellular and organellar membranes

Morphology of Cell Injury – Key Concept • Morphologic changes follow functional changes

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Reversible Injury -- Morphology • Light microscopic changes – Cell swelling (a/k/a hydropic change)

Irreversible Injury -- Morphology • Light microscopic changes – Increased cytoplasmic eosinophilia (loss of

Irreversible Injury – Nuclear Changes • Pyknosis – Nuclear shrinkage and increased basophilia •

Types of Cell Death • Apoptosis – Usually a regulated, controlled process – Plays

Apoptosis • Involved in many processes, some physiologic, some pathologic – Programmed cell death

Apoptosis – Morphologic Features • Cell shrinkage with increased cytoplasmic density • Chromatin condensation

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Types of Necrosis • • • Coagulative (most common) Liquefactive Caseous Fat necrosis Gangrenous

Coagulative Necrosis • Cell’s basic outline is preserved • Homogeneous, glassy eosinophilic appearance due

3 stages of coagulative necrosis (L to R) -- micro

Liquefactive Necrosis • Usually due to enzymatic dissolution of necrotic cells (usually due to

Lung abscesses (liquefactive necrosis) -- gross

Macrophages cleaning liquefactive necrosis -- micro

Caseous Necrosis • Gross: Resembles cheese • Micro: Amorphous, granular eosinophilc material surrounded by

Enzymatic Fat Necrosis • Results from hydrolytic action of lipases on fat • Most

Enzymatic fat necrosis of pancreas -- gross

Gangrenous Necrosis • Most often seen on extremities, usually due to trauma or physical

Fibrinoid Necrosis • Usually seen in the walls of blood vessels (e. g. ,

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Cell Injury I – Cell Injury and Cell Death Dept. of Pathology

Key Concepts • Normal cells have a fairly narrow range of function or steady state: Homeostasis • Excess physiologic or pathologic stress may force the cell to a new steady state: Adaptation • Too much stress exceeds the cell’s adaptive capacity: Injury

Key Concepts (cont’d) • Cell injury can be reversible or irreversible • Reversibility depends on the type, severity and duration of injury • Cell death is the result of irreversible injury

Cell Injury – General Mechanisms • Four very interrelated cell systems are particularly vulnerable to injury: – Membranes (cellular and organellar) – Aerobic respiration – Protein synthesis (enzymes, structural proteins, etc) – Genetic apparatus (e. g. , DNA, RNA)

Cell Injury – General Mechanisms • • Loss of calcium homeostasis Defects in membrane permeability ATP depletion Oxygen and oxygen-derived free radicals

Causes of Cell Injury and Necrosis • Hypoxia – Ischemia – Hypoxemia – Loss of oxygen carrying capacity • • Free radical damage Chemicals, drugs, toxins Infections Physical agents Immunologic reactions Genetic abnormalities Nutritional imbalance

Reversible Injury • Mitochondrial oxidative phosphorylation is disrupted first Decreased ATP – Decreased Na/K ATPase gain of intracellular Na cell swelling – Decreased ATP-dependent Ca pumps increased cytoplasmic Ca concentration – Altered metabolism depletion of glycogen – Lactic acid accumulation decreased p. H – Detachment of ribosomes from RER decreased protein synthesis • End result is cytoskeletal disruption with loss of microvilli, bleb formation, etc

Irreversible Injury • Mitochondrial swelling with formation of large amorphous densities in matrix • Lysosomal membrane damage leakage of proteolytic enzymes into cytoplasm • Mechanisms include: – Irreversible mitochondrial dysfunction markedly decreased ATP – Severe impairment of cellular and organellar membranes

Funky mitochondria

Cell Injury • Membrane damage and loss of calcium homeostasis are most crucial • Some models of cell death suggest that a massive influx of calcium “causes” cell death • Too much cytoplasmic calcium: – Denatures proteins – Poisons mitochondria – Inhibits cellular enzymes

Clinical Correlation • Injured membranes are leaky • Enzymes and other proteins that escape through the leaky membranes make their way to the bloodstream, where they can be measured in the serum

Free Radicals • Free radicals have an unpaired electron in their outer orbit • Free radicals cause chain reactions • Generated by: – Absorption of radiant energy – Oxidation of endogenous constituents – Oxidation of exogenous compounds

Examples of Free Radical Injury • • Chemical (e. g. , CCl 4, acetaminophen) Inflammation / Microbial killing Irradiation (e. g. , UV rays skin cancer) Oxygen (e. g. , exposure to very high oxygen tension on ventilator) • Age-related changes

Mechanism of Free Radical Injury • Lipid peroxidation damage to cellular and organellar membranes • Protein cross-linking and fragmentation due to oxidative modification of amino acids and proteins • DNA damage due to reactions of free radicals with thymine

Morphology of Cell Injury – Key Concept • Morphologic changes follow functional changes

Reversible Injury -- Morphology • Light microscopic changes – Cell swelling (a/k/a hydropic change) – Fatty change • Ultrastructural changes – Alterations of cell membrane – Swelling of and small amorphous deposits in mitochondria – Swelling of RER and detachment of ribosomes

Irreversible Injury -- Morphology • Light microscopic changes – Increased cytoplasmic eosinophilia (loss of RNA, which is more basophilic) – Cytoplasmic vacuolization – Nuclear chromatin clumping • Ultrastructural changes – Breaks in cellular and organellar membranes – Larger amorphous densities in mitochondria – Nuclear changes

Irreversible Injury – Nuclear Changes • Pyknosis – Nuclear shrinkage and increased basophilia • Karyorrhexis – Fragmentation of the pyknotic nucleus • Karyolysis – Fading of basophilia of chromatin

Karyolysis & karyorrhexis -micro

Types of Cell Death • Apoptosis – Usually a regulated, controlled process – Plays a role in embryogenesis • Necrosis – Always pathologic – the result of irreversible injury – Numerous causes

Apoptosis • Involved in many processes, some physiologic, some pathologic – Programmed cell death during embryogenesis – Hormone-dependent involution of organs in the adult (e. g. , thymus) – Cell deletion in proliferating cell populations – Cell death in tumors – Cell injury in some viral diseases (e. g. , hepatitis)

Apoptosis – Morphologic Features • Cell shrinkage with increased cytoplasmic density • Chromatin condensation • Formation of cytoplasmic blebs and apoptotic bodies • Phagocytosis of apoptotic cells by adjacent healthy cells

Apoptosis – Micro

Types of Necrosis • • • Coagulative (most common) Liquefactive Caseous Fat necrosis Gangrenous necrosis

Coagulative Necrosis • Cell’s basic outline is preserved • Homogeneous, glassy eosinophilic appearance due to loss of cytoplasmic RNA (basophilic) and glycogen (granular) • Nucleus may show pyknosis, karyolysis or karyorrhexis

Splenic infarcts -- gross

Infarcted bowel -- gross

Myocardium photomic

Adrenal infarct -- Micro

3 stages of coagulative necrosis (L to R) -- micro

Liquefactive Necrosis • Usually due to enzymatic dissolution of necrotic cells (usually due to release of proteolytic enzymes from neutrophils) • Most often seen in CNS and in abscesses

Lung abscesses (liquefactive necrosis) -- gross

Liver abscess -- micro

Liquefactive necrosis -- gross

Liquefactive necrosis of brain -- micro

Macrophages cleaning liquefactive necrosis -- micro

Caseous Necrosis • Gross: Resembles cheese • Micro: Amorphous, granular eosinophilc material surrounded by a rim of inflammatory cells – No visible cell outlines – tissue architecture is obliterated • Usually seen in infections (esp. mycobacterial and fungal infections)

Caseous necrosis -- gross

Extensive caseous necrosis -- gross

Caseous necrosis -- micro

Enzymatic Fat Necrosis • Results from hydrolytic action of lipases on fat • Most often seen in and around the pancreas; can also be seen in other fatty areas of the body, usually due to trauma • Fatty acids released via hydrolysis react with calcium to form chalky white areas “saponification”

Enzymatic fat necrosis of pancreas -- gross

Fat necrosis -- micro

Gangrenous Necrosis • Most often seen on extremities, usually due to trauma or physical injury • “Dry” gangrene – no bacterial superinfection; tissue appears dry • “Wet” gangrene – bacterial superinfection has occurred; tissue looks wet and liquefactive

Gangrene -- gross

Wet gangrene -- gross

Gangrenous necrosis -- micro

Fibrinoid Necrosis • Usually seen in the walls of blood vessels (e. g. , in vasculitides) • Glassy, eosinophilic fibrin-like material is deposited within the vascular walls