Post on 31-Dec-2015
Cell Injury and Cell Death
Nirush Lertprasertsuke, M.D.
Department of Pathology
Faculty of Medicine,
Chiang Mai University
Cell Injury
• 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
• 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
• Reactive oxygen metabolites (free radicals) damage cells: O(-), OH(-), H2O2– 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
Molecular mechanisms (2)
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
• Coagulative necrosis
• Liquefactive necrosis
• Caseous necrosis
• Fat necrosis
• Gangrenous necrosis
• Fibrinoid necrosis
Coagulative necrosis• 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– 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 ac
ute 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
ApoptosisSettings
• 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
ApoptosisMechanisms
• 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
ApoptosisBiochemical 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
ApoptosisMorphology
• Cell shrinkage• Chromatin condensation• Formation of cytoplasmic blebs and apoptoti
c bodies• Phagocytosis of apoptotic cells/bodies • Single cell or small clusters with intense eosi
nophilic cytoplasm and dense chromatin fragments