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Notes about irreversible injury

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  3. 3. Reversible InjuryEarly stages of injury = mild  Mild damage to cell components including the energy supply  Cell developed morphological changes
  4. 4. Reversible InjuryThe functional and morphologic changes are reversible if the damaging stimulus is removed – Significant structural and functional abnormalities – Injury typically not progressed to severe membrane damage and nuclear dissolution
  5. 5. Reversible InjuryCauses: – Hypoxia = reduced oxydative phosphorilation – ATP depeletion – Damaged plsma membrane
  6. 6. Reversible InjuryThe pattern of cellular changes: 1. Cellular swelling 2. Cellular fatty changes 3. Accumulation of pigments – melanin, bilirubin, iron
  7. 7. 1. Cellular Swelling Manifestation of all forms of injury Difficult to appretiate with the light microscopic = electron microscope – Apparent at the level of the whole organ
  8. 8. 1. Cellular Swelling Pathogenesis 1. Plasma membrane damaged – 2. Diminished ATP & Na+ pump – 3. Na+ increase in cell – 4. Water rush into cell
  9. 9. 1. Cellular Swelling Cells unable to maintain ionic and fluid homeostasis Morphological changes 1. Cloudy swelling 2. Hydrophic vacuolation
  10. 10. 1. Cellular Swelling1. Cloudy swelling – = cells swell, cytoplasm contains coarse granules – = swelling of the membrane bound organnelles – mitochondria (rounded & beaded)2. Hydrophic vacuolation = cytoplasm contains small watery vacuoles = vacuoles represent distended and pinch off or sequestered segments of the ER
  11. 11. 1. Cellular SwellingExamples of the morphological changes: – Following acute cell injury cells are swollen up and cytoplasm is granular – Parenchymatous organs e.g. liver and kidney, are swollen, bulges when cut and has a grey parboiled appearance and is soft in consistensy – The cells assume hydropic or vacuolar when the cell swelling is marked e.g. baloon cells in epidermis in herpes simplex infection – The name cloudy swelling refers to appearance of the cell under microscope
  12. 12. 2. Fatty Changes Accumulation of fat in non-fatty tissues Usually seen in the parenchymatous organs (e.g: liver & kidney), skeletal muscles and heart Causes: – Cell poison: alcohol, chloroform, bacterial – Clinical disorders: anoxia, diabetes mellitus, malnutrition, obesity
  13. 13. 2. Fatty Changes Essential problem: non-fatty tissue unable to metabolise the amount of lipid present in them = fat accumulate within cells!
  14. 14. 2. Fatty Changes These etiologies cause accumulation of fat in the hepatocytes by the following mechanisms: a. Increased uptake of triglycerides into the parenchymal cells b. Decreased use of fat by cells c. Overproduction of fat in cells d. Decreased secretion of fat from the cells
  15. 15. 2. Fatty ChangesEffects of fatty changes» impaired cellular function = due to the pathological process causing the fatty changes, NOT the physical presence of fat within the cell  Liver - very large accumulation of fat do not impair basic liver functions  Rapid or large + fatty myocardium – weak muscle fibers = dilatation of fat = cardiac failure
  16. 16. Increased fat deposition= enlargement of the organ
  17. 17. 3. Accumulation of pigments Pigments can be exogenous or endogenous – Endogenous pigments include melanin, bilirubin, hemosiderin, & lipofuscin – Exogenous pigments include carbon = from outside These pigments can accumulate inside cells in different situations
  18. 18. a. Melanin Melanin is a brownish-black pigment produced by the melanocytes found in the skin Increased melanin pigmentation is caused by suntanning & certain diseases e.g. nevus, or malignant melanoma Decreased melanin pigmentation is seen in albinism & vitiligo
  19. 19. b. Bilirubin Bilirubin is a yellowish pigment, mainly produced during the degradation of hemoglobin Excess accumulation of bilirubin causes yellowish discoloration of the sclerae, mucosae, & internal organs = called jaundice – Causes of jaundice = haemolytic anemia, billiary obstruction & hepatobilliary diseases
  20. 20. c. Hemosiderin Hemosiderin is an iron-containing pigment derived from ferritin Hemosiderin exists normally in small amounts within tissue macrophages of the bone marrow, liver, & spleen as physiologic iron stores It accumulates in tissues in excess amounts in certain diseases = iron overload disorder
  21. 21. c. Hemosiderin 2 types of hemosiderin accumulation – Hemosiderosis • accumulation is primarily within tissue macrophages & not associated with tissue damage
  22. 22. c. Hemosiderin 2 types of hemosiderin accumulation – Hemochromatosis • more extensive accumulation of hemosiderin, often within parenchymal cells, which leads to tissue damage, scarring & organ dysfunction
  23. 23. d. Hemoglobin Intravascular haemolysis – Acute • Appears in urine = dull red color - hematuria – Chronic • Paroxysmal haemoglobinuria
  24. 24. e. Lipofuscin Yellowish brown pigment with a high lipid content Generated by the normal intracellular metabolism of old cellular components = such as old cell membranes
  25. 25. e. Lipofuscin Often found in atrophic cells or in old age – common in the heart muscle, where the term “brown atrophy” of the heart is often applied – also found in liver cells, testes and nerve cells
  26. 26. e. Lipofuscin Seen adjacent to the cell nuclei (perinuclear location) – electron microscope = lipofuscin is usually seen in phagolysosomes (membrane-bound vesicles that contain old cellular debris)
  27. 27. Exogenous Pigmentation develop when small amounts of a foreign substance are embedded in the tissues Introduced by inhalation, ingestion or injection
  28. 28. Exogenous Pigmentation Inhalation – coal dust (carbon) - black, stone dust (silica) – grey, iron, asbestos – particles reach alveoli - disturb broncial cilliary action – produce occupational lung disease = pneumoconiosis
  29. 29. Exogenous Pigmentation Ingestion – Chronic ingestion of metal = silver or lead – Skin has metallic hue, blue line appears on the gum (interaction between lead & hydrogen sulphide)
  30. 30. Argyria
  31. 31. Excessive intake of carrots = lead to yellowish red skin pigmentation by carotene
  32. 32. Exogenous Pigmentation Injection – Tatooing • pigments like Indian ink ,cinnabar and carbon are introduced into the dermis • the pigment is taken up by macrophages and lies permanently in the connective tissue
  34. 34. Irreversible InjuryCell deathWith continuing damage - injury becomes irreversible - cell cannot recover = diesThere are 2 types of cell death – Apoptosis – Necrosis
  35. 35. ApoptosisGreek word = falling off, like leaves from trees in autumnProgrammed cell deathActive, energy dependant A form of cell death in which a programmedsequence of events leads to the elimination ofcells without releasing harmful substances into the surrounding area
  36. 36. ApoptosisPrearranged pathway of cell deathTriggered by variety of specific extracellular and intracellular signalsPart of the balance between life and death of a cell – determine that a cell dies when it is no longer useful or when it may harm the larger organism – Self-defence mechanism - cell infected by pathogens or have genomic alteration = cell destroyed
  37. 37. ApoptosisRapid process – usually affecting single cells scattered in a population of healthy cells – Cells can be eliminated with minimal disruption to adjacent cells – Injurious agents that are capable of producing necrosis can induce apoptosis when given in low dosageEnd result: elimination of cells from tissues without eliciting a tissue response to injury = no inflammatory response!
  38. 38. ApoptosisImportant process in health and disease = eliminate unwanted or abnormal cells – In health: embryogenic and development • Loss of autoreactive response of T cells in the thymus = preventing auto-immune attack • Cyclical hormonal changes of the breast and endometrial tissue
  39. 39. Apoptosis– In disease: • irradiation, viral, infection, action of cytotoxic T cells = rejection of transplanted organs • Tumors = apoptosis & proliferation rates together to control the rate of growth – tumors with high apoptosis rate generally grow slowly
  40. 40. Apoptosis2 stages in apoptosis1)The dying process  Active metabolic changes in the cell, cause cytoplasmic and nuclear condensation and fragmentation  Plasma membrane intact  Cell disintegrates into apoptotic bodies – each surrounded by a plasma membrane and some contain nuclear material
  41. 41. Apoptosis2 stages in apoptosis2)The elimination process – Phagocytosis by surrounding cells followed by rapid digestion*The surrounding cells move together to fill the vacant space, leaving virtually no evidence of the process*The presence of intact plasma membranes arround the apoptotic bodies explain the absence of inflammation
  42. 42. NecrosisGreek word = dead, the stage of dyingMajor pathway of cell deathOnly occur in living organismsAlmost always detrimental and can be fatal morphologic changes that following the celldeath in a living tissue or organ resulting from the progressive degradative activity of catalytic enzymes
  43. 43. NecrosisCauses – Hypoxia – Physical agents (trauma) – Chemical agents (free-radicals) – Immunological injury (hypersensitivity)
  44. 44. Pathogenesisa) begins with an impairment of the cell’s ability to maintain homeostasisb) Leading to an influx of water and extracellular ionsc) Intracellular organelles, most notably the mitochondria, and the entire cell swell and rupture (cell lysis)d) Due to the ultimate breakdown of the plasma membrane, the cytoplasmic contents including lysosomal enzymes are released into the extracellular fluide) Therefore, in vivo, necrotic cell death is often associated with extensive tissue damage resulting in an intense inflammatory response
  45. 45. NecrosisNuclear changes Pyknosis: condensation of chromatin of chromatin and shrinkage of the nucleus Karyorrhexis: fragmentation of the nucleus Karyolysis: dissolution of the nucleus
  46. 46. NecrosisCauses – Hypoxia – Physical agents – Chemical agents – Immunological injury
  48. 48. NecrosisTypes – Coagulative necrosis – Liquefactive necrosis – Fat necrosis – Caseous necrosis – Fibrinoid necrosis