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Cell Injury Patho

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  • 1. LMP 300Y – Lecture 1 Cell injury, adaptation & death Douglas M. Templeton, Ph.D., M.D. doug.templeton@utoronto.ca References Kumar, Cotran & Robbins, Basic Pathology, 7th ed.Saunders, 2003. Apoptosis - Nature, Oct. 12, 2000; Annu. Rev. Pharmacol. Toxicol., 42:259 (2002) Some images from http://medlib.med.utah.edu/WebPath/webpath.html 2002/2003; revised 2005
  • 2. Cell death -- good and bad - good: development, T cell clones, cancer cells - bad: tissue destruction, atrophy Four terms: Necrosis Apoptosis Necrapoptosis Anoikis
  • 3. CAUSES OF CELL INJURY: Internal stresses • metabolic imbalances, nutritional deficiencies or excesses • genetic abnormalities • acquired derangements –> hypoxia, ischemia External • physical agents (heat, cold, radiation, …) • natural toxins, venoms • drugs, "chemicals" (Paracelsus)
  • 4. RESPONSES TO INJURY: • Recovery • Adaptation • Death Depends on mechanism, severity, duration, …
  • 5. Cell injury may be reversible or irreversible …
  • 6. Stages in Cell Injury
  • 7. “Cellular function is lost far before cell death occurs, and the morphologic changes of cell injury (or death) lag far behind both.”
  • 8. "Even at the level of the light microscope, it is apparent that cells exhibit a finite number of morphologic reactions to a wide range of internal and external environmental stresses." "This … implies common biochemical and molecular mechanisms responsible for cell adaptation and failure of adaptation, or cell death."
  • 9. Different cells show different sensitivities/thresholds. Exam ples: • Brain cells, heart cells susceptible to hypoxia and ischemia; liver cells susceptible to chem injury ical . • Calf muscle tolerates 2-3 h of ischemia, cardiac muscle dies in 20-30 min. • Highly differentiated surface epithelial cells of the respiratory tract more susceptible to cigarette smoke than less differentiated basal epithelia. • Nutritional status – glycogen-replete hepatocyte more resistant to ischem than depleted one. ia
  • 10. • Hypoxia - Oxygen deficiency • Ischemia - Impaired blood supply (arterial or venous occlusion) • Infarction - Area of necrosis due to ischemia
  • 11. Some basic types of tissues • Epithelium, endothelium • Connective tissue, fibroblasts • Muscle tissue – smooth, skeletal, cardiac • Nervous tissue • Blood and lymph
  • 12. A Classification of Epithelium • Simple – Simple squamous (endothelium) – Simple cuboidal (renal tubule) – Simple columnar (small intestine) • Stratified squamous – Low keratin (esophagus) – Keratinized (epidermis) • Pseudostratified – Columnar, ciliated (trachea, epididymis) – Transitional (bladder)
  • 13. FOUR VULNERABLE SYSTEMS: • Cell membrane integrity • ATP generation / mitochondrial function • Protein synthesis / enzyme function • Genetic integrity
  • 14. SIX GENERAL MECHANISMS: • ATP depletion (ox/phos or glycolysis) • Oxygen (i) – ischemia/hypoxia • Oxygen (ii) – ROS • Loss of Ca2+ homeostasis • Plasma membrane integrity • Mitochondrial damage
  • 15. ATP O2 ROS Ca2+ Mito. fcn. PM
  • 16. A CENTRAL ROLE OF FREE RADICALS IN CELL DEATH Sources Defences Mitochondrial respiration Glutathione Xanthine oxidase (purine metabolism –> uric acid, O2-.) Catalase (H2O 2) - peroxisomes Peroxisomes (long chain FA –> H2O 2) Mn-superoxide dismutase - mitochondria NADPH oxidase (respiratory burst) Cu,Zn-SOD - cytosol Cyt P450 mixed function oxidase Antioxidants Metal sequestration Metallothionein
  • 17. QuickTime™ and a Photo - JPEG decompressor are needed to see this picture.
  • 18. ADAPTIVE RESPONSES OF CELLS: • Atrophy • Hypertrophy • Hyperplasia • Metaplasia • Storage
  • 19. ATROPHY: Cell shrinkage by loss of substance
  • 20. Cerebral atrophy - Alzheimer disease
  • 21. Testicular Atrophy
  • 22. HYPERTROPHY: Increase in cell (hence organ) size
  • 23. QuickTime™ and a Photo - JPEG decompressor are needed to see this picture.
  • 24. Hypertrophy - normal and gravid uterus QuickTime™ and a Photo - JPEG decompressor are needed to see this picture.
  • 25. QuickTime™ and a Photo - JPEG decompressor are needed to see this picture.
  • 26. HYPERPLASIA: Increase in cell number
  • 27. METAPLASIA: (Reversible) replacement of one differentiated cell type by another
  • 28. QuickTime™ and a Photo - JPEG decompressor are needed to see this picture.
  • 29. STORAGE:
  • 30. Normal Liver
  • 31. Fatty Liver
  • 32. Fatty Liver
  • 33. Hemochromatosis
  • 34. Calcification - Tricuspid valve
  • 35. OVERVIEW i) Atrophy – decreased testosterone –> prostatic atrophy (apoptosis) ii) Hypertrophy – exercise / skeletal muscle; hypertension / cardiac myocyte iii) Hyperplasia – hyperthyroidism, effect of excess TSH on thyroid gland iv) Metaplasia – ciliated epithelium –> squamous epithelium in smoker. (Point for argument: Is the myofibroblast a metaplastic cell?) v) Storage – Gaucher's disease (glucocerebrosidase),Haemochromatosis (Fe), Fatty liver (EtOH)
  • 36. Some terms in the histology of cell injury: Fluid or fat accumulates in vacuoles – cloudy swelling / hydropic degeneration e.g., disruption of ion transport/pumping (loss of ATP –> Na+/K+ ATPase, oxidation of thiols on pumps, disorganization of membrane lipids, …) Fat accumulation – fatty change - fatty acid synthesizing/transporting cells (heart, liver, kidney) - ER membrane damage, ↓FA oxid'n, ↑TG synth., ↓lipoprotein synth., … Irreversible injury: A cell may be irreversibly injured long before any changes are apparent in the microscope. Coagulation necrosis – influx of water and ions, mitochondrial swelling, general loss of membrane integrity, influx of Ca2+ (coagulation of proteins, activation of enzymes), release of lysosomal enzymes (autolysis)
  • 37. Kidney Infarct - coagulative necrosis
  • 38. Cerebral Infarct - liquefactive necrosis
  • 39. Caseous necrosis - tuberculosis
  • 40. APOPTOSIS Membrane blebbing, cell shrinkage, protein fragmentation, chromatin condensation, DNA degradation, engulfment - central role of caspases, cysteine proteases cleaving Asp-Xxx bond - upstream (initiator) and downstream (effector) caspases - may inactivate (e.g., lamins) or activate (e.g., nucleosomal nuclease) substrate
  • 41. Apoptosis vs. Coagulation Necrosis Apoptosis Necrosis Stimulus Physiological (Developmental, Hyppoxia, Toxins Atrophy, …) Selected Pathological Histology Single cells, shrinkage, chromatin Cell swelling, groups of cells, condensation, apoptotic bodies tissue disruption Organelles Intact Swelling of mitochondria & ER Nucleus Chromatin condensation, inter- Disappearance, nucleosomal breaks, laddering Random DNA breaks (karyorrhexis) (karyolysis) Outcome Phagocytosis of apoptotic bodies Inflammation, regeneration or repair by fibrosis
  • 42. Extrinsic Intrinsic
  • 43. Bcl-2 family members – balance between pro-apoptotic (e.g., Bax, Bak) and anti (e.g., Bcl-2, Bcl-x) determines outcome. Hydrophobic C-terminal domain localizes them to outer mitochondrial membrane. With other proteins, form channels to facilitate release of Cyt c. Mitochondrial permeability transition pore – MPTP
  • 44. Caspases are synthesized as inactive zymogen; pro-domain, p20, and p10 domains. Activated by cleavage between p20 and p10, and pro- domain and p20. Active as tetramer of 2 p10 and 2 p20 domains. Three models for caspase activation. i) caspase cascade, e.g. downstream effectors caspase-3, -6, -7 ii) induced proximity, e.g., on ligand binding CD95 receptors aggregate to form signaling complexes, which through adapter proteins bring about high local concentrations of procaspase-8 iii) association with a regulatory subunit, e.g., caspase-9 and Apaf-1
  • 45. DNA damage can initiate apoptosis. Dual function of p53: If damage detected, cell cycle arrest. If damage not repaired, iniates apoptosis. How is damage sensed? Proteins of the ATM (ataxia telangiectasia- mutated) and DNA-PK contain DNA binding domains and protein kinase activity. Both phosphorylate p53.
  • 46. Signals for ingestion: i) altered sugars recognized by lectins on macrophages ii) Thrombospondin – secreted by macrophages, binds to apoptotic cells (mechanism not known), then macrophage integrins bind to thrombospondin. iii) phosphatidyl serine (annexin V)
  • 47. Apoptosis can be suppressed • at the level of caspases • at the level of the mitochondria • by ionic control
  • 48. QuickTime™ and a GIF decompressor are needed to see this picture.
  • 49. Necrapoptosis – Lemasters, Am. J. Physiol. 276: G1-G6 (1999). Cell balanced between apoptosis and necrosis depending on production of ATP. Anoikis – Frisch & Ruoslahti, Current Opin. Cell Biol. 9: 701-706 (1997). "Homelessness". Apoptosis initiated by detachment of epithelial cell from matrix.

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