1. Cell Injury and Cell Death Ashish kham budha magar

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

19. Depletion of ATP Mechanisms of Cell Injury Na + K + ATPase ( Na -pump ) , Ca 2+ Mg 2+ ATPases ( Ca -pump ) Causes Hypoxia, Ischemia Chemical Injury Membrane transport Protein synthesis, Lipogenesis etc ATP

21. Mechanisms of Cell Injury Depletion of ATP Na + K + Ca 2+

22. Mitochondrial Damage Mechanisms of Cell Injury Causes Hypoxia, Toxins Cytosolic Ca 2+ Oxidative stress Lipid breakdown product

25. Mechanisms of Cell Injury Mitochondrial Damage

26. Influx of Intracellular Calcium and Loss of Calcium Homeostasis Mechanisms of Cell Injury

27. Mechanisms of Cell Injury

30. A CENTRAL ROLEOFFREERADICALSINCELL DEATH Sources Mitochondrial respiration Xanthine oxidase (purine metabolism –> uric acid, O2-.) Peroxisomes (long chain FA –> H2O2) NADPH oxidase (respiratory burst) Cyt P450 mixed function oxidase Defense Glutathione Catalase (H2O2) – peroxisomes Mn-superoxide dismutase – mitochondria Cu,Zn-SOD - cytosol Antioxidants Metal sequestration Metallothionein

37. Superoxide dismutase (SOD)

40. Cellular and biochemical sites of damage in cell injury

64. HISTOLOGIC FEATURES OF COAGULATIVE NECROSIS Normal cell Reversible cell injury with cytoplasmic & organelle swelling, blebbing & ribosome detachment Irreversible cell injury with rupture of membrane & organelles, & nuclear pyknosis Karyorrhexis Karyolysis

69. 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.

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

74. Coagulative and liquefactive necrosis A, Kidney infarct exhibiting coagulative necrosis B, A focus of liquefactive necrosis in the kidney Figure 1-19 Coagulative and liquefactive necrosis. A, Kidney infarct exhibiting coagulative necrosis, with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture. B, A focus of liquefactive necrosis in the kidney caused by fungal infection. The focus is filled with white cells and cellular debris, creating a renal abscess that obliterates the normal architecture.

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

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

79. This is the gross appearance of caseous necrosis in a hilar lymph node infected with tuberculosis. The node has a cheesy tan to white appearance. Caseous necrosis is really just a combination of coagulative and liquefactive necrosis that is most characteristic of granulomatous inflammation

80. T uberculous granuloma showing an area of central necrosis, epithelioid cells, multiple Langhans-type giant cells, and lymphocytes.

82. Foci of fat necrosis with saponification in the mesentery

83. Ischemic injury

84. Mechanisms of Cell Injury Ischemic injury

85. 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

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

90. Apoptosis vs. Coagulation Necrosis Cell size Enlarged Reduced Nucleus Pyknosis / karyorrhexis / karyolysis Fragmentation Plasma membrane Disrupted Intact Cellular contents Enzymatic digestion Intact Inflammation Frequent None Physiologic/pathologic Pathologic Physiologic Feature Necrosis Apoptosis

91. Labeled (1) are some of the major inducers of apoptosis. These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand), withdrawal of growth factors or hormones, and injurious agents (e.g., radiation). (2) Control and regulation are influenced by members of the Bcl-2 family of proteins, which can either inhibit or promote the cell's death. (3) Executioner caspases activate latent cytoplasmic endonucleases and proteases that degrade nuclear and cytoskeletal proteins. This results in a cascade of intracellular degradation, including fragmentation of nuclear chromatin and breakdown of the cytoskeleton. (4) The end result is formation of apoptotic bodies containing intracellular organelles and other cytosolic components; these bodies also express new ligands for binding and uptake by phagocytic cells.

105. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 October 2005 05:51 PM) © 2005 Elsevier Lipid circulation

106. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 October 2005 05:51 PM) © 2005 Elsevier Fatty liver

108. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 October 2005 05:51 PM) © 2005 Elsevier

110. Protein reabsorption droplets in the renal tubular epithelium. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 October 2005 05:51 PM) © 2005 Elsevier

120. Different cells showdifferent sensitivities/thresholds. Examples: •Brain cells, heart cells susceptible to hypoxiaand ischemia; liver cells susceptible to chemical injury. •Calf muscletolerates 2-3h of ischemia, cardiacmuscle diesin20-30 min. •Highly differentiated surface epithelial cellsof therespiratorytract more susceptible to cigarette smokethan less differentiated basal epithelia. •Nutritional status – glycogen-replete hepatocyte moreresistant to ischemiathan depleted one

121. • Hypoxia - Oxygen deficiency • Ischemia - Impaired blood supply (arterial or venous occlusion) • Infarction - Area of necrosis due to ischemia

122. • 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)

123. FOUR VULNERABLE SYSTEMS: 􀀀• Cell membrane integrity 􀀀• ATP generation / mitochondrial function 􀀀• Protein synthesis / enzyme function 􀀀• Genetic integrity

124. 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

125. Wake up