cell injury and cell death nirush lertprasertsuke, m.d. department of pathology faculty of medicine,...

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