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