Transcript Cell Injury and Cell Death

Cell Injury and Cell Death
Nirush Lertprasertsuke, M.D.
Department of Pathology
Faculty of Medicine,
Chiang Mai University
Cell Injury
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Normal cell: homeostasis
Sublethal injury: reversible injury
Irreversible injury
Cell death
Normal homeostasis
• Genetic programs
– metabolism
– differentiation
– specialization
• Constraints of neighboring cells
• Availability of metabotic
substrates
Cellular Responses to Injury
• Acute cell injury
• Reversible cell injury
• Cell death
• Subcellular alterations in sublethal and
chronic injury
• Cellular adaptations: ~trophy/~plasia
• Intracellular accumulations
• Pathologic calcifications
• Cell aging
Causes of cell injury
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Oxygen Deprivation: hypoxia/ischemia
Physical agents
Chemical agents and drugs
Infectious agents
Immunologic reactions
Genetic derangements
Nutritional imbalances: self-imposed
Principles of cell injury
• Stimulus: type, duration, severity
• Cell: type, state, adaptability
• Cellular targets
– cell membranes: integrity
– mitochondria: aerobic respiration
– cytoskeleton: protein synthesis
– cellular DNA: genetic apparatus
• Structural and biochemical elements
Molecular mechanisms (1)
• ATP loss causes failure of biosynthesis and
ion pumps: ‘cloudy swelling’
• Cytosolic free Ca is a potent destructive
agents: activates intracellular enzymes and
causes cell death
– protein kinases: phosphorylation of protein
– phospholipases: membrane damage
– proteases: cytoskeletal disassembly
Molecular mechanisms (2)
• Reactive oxygen metabolites (free radicals)
damage cells: O(-), OH(-), H2O2
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peroxidation of lipids (cell memb.)
thiol-containing protein damage (ion pump)
DNA damage (protein synthesis)
mitochondrial damage (Ca influx)
• Membrane and cytoskeletal damage
– immune-mediated injury
Morphology of Reversible cell injury
• Ultrastructural damage to mitochondria
– Low-amplitude swelling
– (High-amplitude swelling: irreversible)
• Swelling of cellular organelles: hydropic
degeneration/cloudy swelling
• Fatty change: sublethal impairment of
metabolism: liver
Morphology of Cell death
• Lysis: Disintegration of cellular structure
followed by dissolution
• Necrosis: spectrum ofmorphologic
changes that follow cell death in living
tissue
• Apoptosis: “programmed cell death”elimination of unwanted host cells
Necrosis
• Concurrent processes:
– Enzymic digestion: lysis
• autolysis: lysosomes of the dead cells
• heterolysis: immigrant leukocytes
– Denaturation of proteins
• Intense eosinophilia
• Nonspecific DNA breakdown
– Pyknosis
– Karyorhexis
– Karyolysis
Patterns of Necrosis
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Coagulative necrosis
Liquefactive necrosis
Caseous necrosis
Fat necrosis
Gangrenous necrosis
Fibrinoid necrosis
Coagulative necrosis
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Dead tissue: firm and pale
Intact c.outlines and t.architecture
Intracellular acidosis denatures enzymes
Occlusion of arterial supply
Enzymes used in Dx of tissue damage
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Myocardium: CK (MB isoform), AST, LDH
Hepatocytes: ALT
Striated muscle: CK (MM isoform)
Exocrine pancreas: amylase
Liquefactive necrosis
• Semi-liquid viscous tissue
• Potent hydrolytic enzymes
• Examples
– Hypoxic dead in the CNS: lysosomal enzymes
of the neurons and the relative lack of
extracellular structural protein
– Bacterial infection: pus
• neutrophil hydrolases: acute inflammation
Caseous necrosis
• Soft and white: like cream cheese
• Amorphous eosinophilic mass, loss of
tissue architecture
• Associated with granulomatous
inflammation(reaction) in Tuberculosis
Fat necrosis
• Hard yellow-gray material: fat tissue
• Examples:
– Retroperitoneal fat necrosis associated with
acute of the pancreas
– Traumatic fat necosis: breast, buttock
Gangrenous necosis
• Mummified darkened and shrinkage
• Coagulative necrosis only or modified by
liquefactive necrosis
• Dry gangrene: limb (lower leg/toe)
• Wet gangrene: hollow viscera (GI tract)
– hemorrhage within the tissue
Fibrinoid necrosis
• Deposits of fibrin to the wall of necrotic
vessels
• Causes:
– Vasculitis: autoimmune disease
– Hypertension
Apoptosis
Settings
• During development
• Homeostatic mechanism to maintain cell
populations in tissue: involution
• Defense mechanism e.g. immune reaction
• Injury
– viral infection
– low doses of injurious stimuli
• Aging
Apoptosis
Mechanisms
• Signaling pathways
– Transmembrane signals: hormone, cytokines
– Intracellular signaling: heat, viral infection
• Control and integration stage: adaptor
proteins, Bcl-2, p53, granzyme B
• Execution phase: endonuclease activation,
catabolism of cytoskeleton
• Removal of dead cells
Apoptosis
Biochemical features
• Protein Cleavages:cysteine proteases
– caspases:
• nuclear scaffold
• cytoskeletal proteins
• Protein cross-linking: transglutaminase
• DNA breakdown: endonucleases
– 50~300 kb and then 180~200 bp
• Phagocytic recognition
– phosphatidylserine
Apoptosis
Morphology
• Cell shrinkage
• Chromatin condensation
• Formation of cytoplasmic blebs and
apoptotic bodies
• Phagocytosis of apoptotic cells/bodies
• Single cell or small clusters with intense
eosinophilic cytoplasm and dense
chromatin fragments