Cell Injury and Cell Death

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Cell Injury and Cell Death

• Nirush Lertprasertsuke, M.D.
• Department of Pathology
• Faculty of Medicine,
• Chiang Mai University

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Cell Injury

• Normal cell homeostasis
• Sublethal injury reversible injury
• Irreversible injury
• Cell death

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Normal homeostasis

• Genetic programs
• metabolism
• differentiation
• specialization
• Constraints of neighboring cells
• Availability of metabotic substrates

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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

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Causes of cell injury

• Oxygen Deprivation hypoxia/ischemia
• Physical agents
• Chemical agents and drugs
• Infectious agents
• Immunologic reactions
• Genetic derangements
• Nutritional imbalances self-imposed

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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

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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

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Molecular mechanisms (2)

• 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

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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

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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

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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

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Patterns of Necrosis

• Coagulative necrosis
• Liquefactive necrosis
• Caseous necrosis
• Fat necrosis
• Gangrenous necrosis
• Fibrinoid necrosis

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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

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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

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Caseous necrosis

• Soft and white like cream cheese
• Amorphous eosinophilic mass, loss of tissue
  architecture
• Associated with granulomatous inflammation(reactio
  n) in Tuberculosis

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Fat necrosis

• Hard yellow-gray material fat tissue
• Examples
• Retroperitoneal fat necrosis associated with
  acute of the pancreas
• Traumatic fat necosis breast, buttock

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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

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Fibrinoid necrosis

• Deposits of fibrin to the wall of necrotic
  vessels
• Causes
• Vasculitis autoimmune disease
• Hypertension

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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

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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

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ApoptosisBiochemical features

• Protein Cleavagescysteine proteases
• caspases
• nuclear scaffold
• cytoskeletal proteins
• Protein cross-linking transglutaminase
• DNA breakdown endonucleases
• 50300 kb and then 180200 bp
• Phagocytic recognition
• phosphatidylserine

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ApoptosisMorphology

• 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

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