1 / 48

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. Normal cell: homeostasis Sublethal injury: reversible injury Irreversible injury Cell death. Normal homeostasis. Genetic programs metabolism

Download Presentation

Cell Injury and Cell Death

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.


Presentation Transcript

  1. Cell Injury and Cell Death Nirush Lertprasertsuke, M.D. Department of Pathology Faculty of Medicine, Chiang Mai University

  2. Cell Injury • Normal cell: homeostasis • Sublethal injury: reversible injury • Irreversible injury • Cell death

  3. Normal homeostasis • Genetic programs • metabolism • differentiation • specialization • Constraints of neighboring cells • Availability of metabotic substrates

  4. 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

  5. Causes of cell injury • Oxygen Deprivation: hypoxia/ischemia • Physical agents • Chemical agents and drugs • Infectious agents • Immunologic reactions • Genetic derangements • Nutritional imbalances: self-imposed

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. Patterns of Necrosis • Coagulative necrosis • Liquefactive necrosis • Caseous necrosis • Fat necrosis • Gangrenous necrosis • Fibrinoid necrosis

  13. 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

  14. 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

  15. Caseous necrosis • Soft and white: like cream cheese • Amorphous eosinophilic mass, loss of tissue architecture • Associated with granulomatous inflammation(reaction) in Tuberculosis

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

  17. 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

  18. Fibrinoid necrosis • Deposits of fibrin to the wall of necrotic vessels • Causes: • Vasculitis: autoimmune disease • Hypertension

  19. 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

  20. 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

  21. 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

  22. 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

More Related