1.1 Cell Injury and Cell Death.pptx

1. Adapted Cell + Stress Injury Normal cell Reversibly injured cell Irreversibly Injured cell Dead cell Apoptosis Necrosis - Stress Overview

4. Cell injury If the limits of adaptive responses are exceeded or if cells are exposed to injurious agents or stress, deprived of essential nutrients or become compromised by mutations that affect essential cellular constituents a sequence of events follows that is termed cell injury

5. Causes of Cell Injury...... Oxygen Deprivation Physical Agents Chemical Agents and Drugs Infectious Agents Immunologic Reactions Genetic Derangements Nutritional Imbalances

6. Oxygen Deprivation Hypoxia – deficiency of oxygen Ischemia – loss of blood supply (arterial flow or reduced venous drainage) Causes of Cell Injury

7. Physical Agents Mechanical trauma Extremes of temperature – burns, deep cold Radiation Electric shock Causes of Cell Injury

8. Chemical Agents and Drugs  Hypertonic concentration of salt – deranging electrolyte homeostasis  Poisons – arsenic, cyanide, or mercuric salts  Insecticides and Herbicides  Air pollutant – carbon monoxide  Occupational hazard – asbestos  Alcohol and Narcotic drugs Causes of Cell Injury

9. Infectious Agents Parasites Fungi Bacteria Rickettsiae Viruses Causes of Cell Injury

10. Immunologic Reactions Anaphylactic reaction to foreign protein or drug Reactions to endogenous self-antigens – autoimmune diseases Causes of Cell Injury

11. Genetics Derangements Congenital malformation – Down syndrome Decreased life of red blood cell – Thalassemia, Sickle cell anemia Inborn errors of metabolism Causes of Cell Injury

12. Nutritional Imbalances Protein-calorie deficiencies Vitamin deficiencies Anorexia nervosa Excesses of lipids – Obesity, Atherosclerosis Metabolic diseases – Diabetes Causes of Cell Injury

13. Mechanisms of Cell Injury  Depletion of ATP  Mitochondrial Damage  Influx of Intracellular Calcium and Loss of Calcium Homeostasis  Accumulation of Oxygen-Derived free radical (Oxidative stress)  Defects in Membrane Permeability  Damage to DNA and Proteins

14. Mechanisms of Cell Injury Depletion of ATP Na+K+ATPase (Na-pump) Ca2+Mg2+ATPases (Ca-pump) Causes  Hypoxia, Ischemia  Chemical Injury Membrane transport Protein synthesis, Lipogenesis etc ATP

15. Na + K+ Ca2+ Mechanisms of Cell Injury Depletion of ATP

16. Mitochondrial Damage Mechanisms of Cell Injury Causes  Hypoxia, Toxins  Cytosolic Ca2+  Oxidative stress (ROS)

17. Mitochondrial Damage Mechanisms of Cell Injury • Mitochondrial permeability transition pore (formation of high-conductance channel) • Leakage of Cytochrome c into cytosol •Abnormal oxidative phosphorylation and ROS formation. ATP production Mitochondrial Oxidative Phosphorylation

18. Mechanisms of Cell Injury Mitochondrial Damage

19. Influx of Intracellular Calcium and Loss of Calcium Homeostasis Mechanisms of Cell Injury  Opening of mitochondrial permeability transition pore and failure of ATP generation.  Activation of many enzymes with potentially deleterious effects on cells.  Induction of apoptosis by direct activation of caspases and by increasing mitochondrial permeability.

20. Mechanisms of Cell Injury

21. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)  The Oxidation-Reduction reaction (normal metabolic processes) -superoxide anion (O2 , ONE ELECTRON) -hydrogen peroxide (H2O2, TWO ELECTRON) -hydroxyl ion (OH ,Three electrons) Mechanisms of Cell Injury

22. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)  Absorption of radiant energy (ultraviolet light, X-ray) Mechanisms of Cell Injury H20 Ionizing radiation OH H

23. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress)  Transition Metals – iron, copper Mechanisms of Cell Injury H202 OH- OH Fe3+ Fe2+ “Fenton reaction”

24. Continue……  Rapid brust of ROS production in activated leukocytes during inflammation.  Enzymatic metabolism of exogenous chemicals or drugs generate free radicals. (ccl4 generate .ccl3 )  Nitric oxide can act as free radical which generated by macrophages, endothelial cells, neurons.

25. Effects of the free radicals on cell injury  Lipid peroxidation of Membranes - Plasma membrane - Organellar membrane Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Mechanisms of Cell Injury Double bonds in unsaturated fatty acids membrane damage

26. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Mechanisms of Cell Injury Effects of the free radicals  Oxidative modification of proteins -Oxidation of amino acid side chains Protein-protein cross-linkages -Oxidation of the protein backbone Protein fragmentation  Damage active sites of enzymes  Disrupts structural conformation of proteins  Enhances protein degradation

27. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Mechanisms of Cell Injury Effects of the free radicals  Lesions in DNA  DNA single and double-strand break Cross linking of DNA strand DNA fragmentation

28. Superoxide dismutase (SOD)

31. Defects in Membrane Permeability  Decreased phospholipid synthesis Mitochondrial dysfunction or hypoxia  Increased phospholipid breakdown by phospholipases  Cytoskeletal abnormalities by proteases activation  Reactive oxygen species Lipid peroxidaton Mechanisms of Cell Injury Mechanism of Membrane damage

32. Cellular and biochemical sites of damage in cell injury

33. Cell Injury Cell Injury – Reversible – Irreversible Cell Death – Necrosis – Apoptosis

34. Morphology of Cell Injury  Plasma membrane alteration  Mitochondrial Changes  Dilation of Endoplasmic reticulum  Nuclear Alteration Reversible Injury  Cellular swelling  Fatty change

36. Cellular swelling Normal Liver cells Swollen Liver cells

37. Necrosis Necrosis refers to a spectrum of morphologic changes that follow cell death in living tissue largely resulting from the denaturation of intracellular proteins and enzymatic digestion of lethally injured cell.

38. Morphology of Necrotic Cells  Increased Eosinophilia - loss of RNA (basophilia) - denatured cytoplasmic protein  Nuclear Changes - Pyknosis - Karyorrhexis - Karyolysis  Myelin figure : From damaged cell membrane – large, whorled phospholipid mass

39. Nuclear change  Karyolysis: Basophilia of chromatin fade due to loss of DNA.  Pyknosis : Nuclear shrinkage and increased basophilia.  Karyorrhexis: Fragmentation of pyknotic nucleus.

40. Morphologic pattern of Necrotic Cell  Coagulative necrosis  Liquefactive necrosis  Gangrenous necrosis  Caseous necrosis  Fat necrosis  Fibrinoid necrosis

41. Morphologic pattern of Necrotic Cell  Coagulative Necrosis: Architecture of dead tissue preserved. – protein denatures – proteolysis inhibited Esonophilic , anucleated cells persists. Example: Ischaemia leads to coagulative necrosis in all organs except brain.

42. This is an example of coagulative necrosis. This is the typical pattern with ischemia and infarction (loss of blood supply and resultant tissue anoxia). Here, there is a wedge-shaped pale area of coagulative necrosis (infarction) in the renal cortex of the kidney.

43. Ischemic necrosis of the myocardium A, Normal myocardium. B, Myocardium with coagulation necrosis

44. Morphologic pattern of Necrotic Cell  Liquefactive Necrosis : Digestion of dead cells and transformation of tissue into liquid viscous mass.  Focal bacterial (or fungal) infections Accumulation of inflammatory cells and enzymes liberation necrotic materials is creamy yellow called PUS.  Hypoxic death of cells within CNS

45. The liver shows a small abscess here filled with many neutrophils. This abscess is an example of localized liquefactive necrosis

46. Coagulative and Liquefactive necrosis A, Kidney infarct exhibiting coagulative necrosis B, A focus of liquefactive necrosis in the kidney

47. Morphologic Pattern of Necrotic Cell  Caseous necrosis:  Example: Tuberculous infection  Gross appearance: cheese like ( friable white like)  Microscopic – Structureless collection of lysed cells and amorphous granular debris enclosed within a inflammatory border GRANULOMA

48. A tuberculous lung with a large area of caseous necrosis

49. Tuberculous granuloma showing an area of central necrosis, epithelioid cells, multiple Langhans’-type giant cells, and lymphocytes.

50. Fat Necrosis Acute pancreatitis : Resulting from release of activated pancreatic lipases Lipase split TG into FA Fat saponification ( FA combines with calcium to produce chalky white areas)

51. Foci of fat necrosis with saponification in the mesentery

52. Gangrenous Necrosis  Typically coagulative necrosis  Generally occurs in lower limb due to ischaemia.  Bacterial infection cause liquefactive necrosis called wet gangrene.

53. Fibrinoid Necrosis Special form of necrosis Occur in immune reactions involving blood vessels Immune complexs together with fibrin leaked out of vessels Bright pink amorphous appearance.

55. Ischemic injury

56. Mechanisms of Cell Injury Ischemic injury

57. Figure: Sequence of events leading to fatty change and cell necrosis in carbon tetrachloride (CCl4) toxicity. RER, rough endoplasmic reticulum; SER, smoothendoplasmic reticulum. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 October 2005 05:23 PM) © 2005 Elsevier Chemical injury

58. Ischemic- Reperfusion injury How it occurs?  Oxidative stress: Generation of ROS Intracellular calcium overload Inflammation : Cytokines release Complement activation

59. Apoptosis  Pathway of Cell death that is induced by a tightly regulated suicide program in which cells destined to die activate intrinsic enzymes that degrade cells own nuclear DNA and nuclear and cytoplasmic proteins. “Programmed Cell Death”  Causes of Apoptosis - Physiologic situations - Pathologic conditions

60. Morphology of Apoptosis Cell shrinkage Chromosome condensation Formation of cytoplasmic blebs and apoptotic bodies Phagocytosis of apoptotic cells or cell bodies

61. Apoptosis in Physiologic Situations  Programmed destruction of cell during embryogenesis  Hormone-dependent involution - endometrial cells (menstrual cycle)  Cell deletion in proliferating cell population  Death of host cells - neutrophils  Elimination of self reactive lymphocyte

62. Apoptosis in Pathologic Conditions  Cell death produced by injurious stimuli – radiation, cytotoxic drug  Accumulation of misfolded proteins ER stress  Cell injury in certain viral diseases – viral hepatitis  Pathologic atrophy  Cell death in tumors, transplants rejection

64. Mitochondrial pathway

65. Dysregulated apoptosis Defective apoptosis and increased cell survival:  Malignancy  Autoimmune disorder Increased apoptosis and excessive cell death:  Neurodegenerative diseases Ischemic injury Death of virus infected cells

66. Necroptosis Hybrid form of cell death that shares aspects of both necrosis and apoptosis.  Morphologically resembles necrosis but mechanistically it is genetically programmed cell death.  Programmed necrosis Caspase independent programmed cell death but dependent on RIP1 and RIP3 complex signaling.

67. Examples of necroptosis  Formation of mammalian bone growth plate.  Cell death in steatohepatitis, acute pancreatitis, reperfusion injury, neurodegenerative dieases.  Host defense against certain virus: cytomegalovirus. Pyroptosis  Another programmed cell death occurs in cells infected by microbes.  Accompanied by release of fever inducing cytokine IL-1 and it bears some similarities with apoptosis.  Activation of caspase-1 and generates IL-1 and cause cell death.

69. Intracellular Accumulations Manifestation of “metabolic derangements” characterized by intracellular accumulation of abnormal amounts of various substances that may be harmless or varying degrees of injury. Types: Normal cellular component: water, lipid, proteins,CHO. Abnormal substance:  Exogenous: Minerals or infected agents products  Endogenous: Abnormal metaboloic products.

70. Mechanisms of intracellular accumulations (1)abnormal metabolism (2)alterations in protein folding and transport (3)deficiency of critical enzymes (4)inability to degrade phagocytosed particles

71. Lipids  Accumulation of Lipids - Triglycerides - Cholesterol/ Cholesterol ester - Phospholipid A. Steatosis (fatty change) Abnormal accumulation of triglycerides within liver parenchymal cells – fatty liver in chronic alcoholism

74. Lipids B. Cholesterol and Cholesterol Esters: Atherosclerosis : Accumulation of cholesterol-laden macrophage (foam cell) and smooth muscle cells in the intima of aorta and arteries . Cholesterolosis : Accumulation of foam cells in the lamina propria of gallbladder. Xanthomas: Foam cells in subepithelial connective tissue of skin and tendons. Niemann-Pick diseases type –C: Choleserol accumulation in multiple organs.

76. Proteins Accumulation of protein droplets in proximal renal tubule : Renal disease  Defective intracellular transport and secretion of protein : Alpha 1 antitrypsin deficiency.  Accumulation of cytoskeletal proteins: Keratin, vimentin  Abnormal proteins aggregation : Amyloidosis

78. Glycogen “Patients with abnormal metabolism of glucose or glycogen”  Diabetes mellitus: disorder of glucose metabolism - glycogen accumulate in epithelial cells of renal tubules, liver cells, beta-cells of the islets of Langerhans heart muscle cells

79.  Glycogen storage disease (Glycogenosis) - genetic diseases - defect of enzymes in the synthesis or breakdown of glycogen accumulation cell injury death Glycogen

80. Pigments  Exogenous pigments Carbon ( anthracosis) Coal dust ( pneumoconiosis) Tattooing: Localized exogenous pigmentation.

81. Pigments  Endogenous pigment Lipofuscin – Insoluble pigment ,found in liver and heart of aging patients or severe malnutrition. Melanin – Brown black colour Hemosiderin – Golden yellow colour

82. Pathologic Calcification Abnormal tissue deposition of Calcium Salts Two forms 1. Dystrophic calcification 2. Metastatic calcification

83. Pathologic Calcification  Dystrophic Calcification - Area of tissue necrosis - Aging or damage heart valve - Atherosclerosis

84.  Metastatic Calcification Occur in normal tissue in “hypercalcemia” Site : Gastric mucosa, kidneys, lungs, systemic arteries, pulmonary veins. Pathologic Calcification Hypercalcemia • Hyperparathyroidism • Resorption of bone tissue • Renal failure •Vitamin D related disorder

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1.1 Cell Injury and Cell Death.pptx

1.1 Cell Injury and Cell Death.pptx

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1.1 Cell Injury and Cell Death.pptx