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Cell injuryadaptation 1

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Cell injuryadaptation 1

  1. 1. Cell injuryCell injury && Adaptation -1Adaptation -1 Dr.CSBR.Prasad, M.D. CSBRP-V3-Dec-2011
  2. 2. Case-1 • A 45 yo male with a chronic smoking history suddenly developed chest pain after a meal. • Pain was retrosternal and radiating to left arm along the ulnar to the tip of left little finger • After 6 hours of travelling he reached a cardiac care center where Chest x-ray, ECG and some blood tests were done CSBRP-V3-Dec-2011
  3. 3. Case-2 • 25yo male developed fever associated with jaundice • He had a tender hepatomegaly • Serum bilirubin was 7.0mg/dl • Liver enzymes are enormously elevated CSBRP-V3-Dec-2011
  4. 4. Divisions in the study of Pathology • General pathology • Systemic pathology Basic reactions of cells and tissues to abnormal stimuli that underlie all diseases Specific responses of specialized organs and tissues to stimuli CSBRP-V3-Dec-2011
  5. 5. The four aspects of disease process 1. Etiology (cause) 2. Pathogenesis (mechanism of disease) 3. Morphological changes (structural alterations) 4. Functional consequences (clinical significance) CSBRP-V3-Dec-2011
  6. 6. Rudolf Virchow [Father of Modern Pathology] ““Virtually all forms ofVirtually all forms of tissue injury starts withtissue injury starts with molecular or structuralmolecular or structural alterations in CELLS”alterations in CELLS” CSBRP-V3-Dec-2011
  7. 7. Subcellular compartments:Subcellular compartments: 1. Nucleus 2. Mitochondria 3. ER 4. Golgi apparatus 5. Lysosomes 6. Cytosol CSBRP-V3-Dec-2011
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  10. 10. HomeostasisHomeostasis When the cell is functioning properly it’s said to be in a “steady statesteady state” i.e. it can handle normal physiological demands CSBRP-V3-Dec-2011
  11. 11. TermsTerms • Cell injuryCell injury • AdaptationsAdaptations CSBRP-V3-Dec-2011
  12. 12. Cell injuryCell injury • Reversible injuryReversible injury 1-Cell swelling 2-Fatty change 3-Mitochondrial swelling 4-ER disruption 5-Membrane blebs 6-Cytoskeleton disruption • Irreversible injuryIrreversible injury 1-Apoptosis 2-Necrosis CSBRP-V3-Dec-2011
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  15. 15. Causes of injuryCauses of injury 1. Ischemia / hypoxia 2. Physical agents 3. Chemical agents 4. Infections 5. Immune reactions 6. Gene defects 7. Nutritional imbalances CSBRP-V3-Dec-2011
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  17. 17. Ischemic & Hypoxic injuryIschemic & Hypoxic injury CSBRP-V3-Dec-2011
  18. 18. ISCHEMIAISCHEMIA HYPOXIAHYPOXIA Blood flowBlood flow Decreased due toDecreased due to vascular occlusionvascular occlusion Flow is normalFlow is normal OO22 tensiontension NormalNormal LowLow Delivery ofDelivery of substratessubstrates DecreasedDecreased NormalNormal Anerobic glycolysisAnerobic glycolysis Ceases faster as there isCeases faster as there is no substrate deliveryno substrate delivery Continues for a muchContinues for a much more longer timemore longer time Tissue injuryTissue injury Occurs with in a shortOccurs with in a short timetime Takes longer timeTakes longer time Note:Note: Ischemia injures tissues faster than hypoxia.Ischemia injures tissues faster than hypoxia. Differences between Ischemic and Hypoxic injuryDifferences between Ischemic and Hypoxic injury CSBRP-V3-Dec-2011
  19. 19. Ischemic & Hypoxic injuryIschemic & Hypoxic injury Decreased oxidative phosphorylation inDecreased oxidative phosphorylation in mitochondria [mitochondria [effecteffect: low ATP levels]: low ATP levels] Effects of Low ATP levels:Effects of Low ATP levels: 1.< activity of Na+ pump [Link] 2.> glycolysis (< intracellular glycogen) 3.Lowered intracellular pH (acidosis) 4.Detachment of ribosomes (< protein synthesis) DD Ischemia / Hypoxia CSBRP-V3-Dec-2011
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  23. 23. IschemiaIschemia // Reperfusion injuryReperfusion injury • It represents exaggerated / acceleratedexaggerated / accelerated injuryinjury that occurs when blood flow is restored contrary to the expectation of recovery • It’s seen especially in myocardium and brain CSBRP-V3-Dec-2011
  24. 24. IschemiaIschemia // Reperfusion injuryReperfusion injury MechanismsMechanisms: • Reperfusion results in high concentration of Ca+ in the environment which cannot be handled by the injured cell • Reperfusion results in augmented recruitment of inflammatory cells to the injured area with resultant >levels of reactive oxygen species • Antioxidant defence mechanisms are not well restored CSBRP-V3-Dec-2011
  25. 25. Free radical – induced cell injuryFree radical – induced cell injury CSBRP-V3-Dec-2011
  26. 26. Free radical – induced cell injuryFree radical – induced cell injury What are free radicals?What are free radicals? • They are a chemical species with a single unpaired electron in an outer orbital • They are extremely unstable • They readily react with organic & inorganic chemicals • With in the cell they attack – Nucleic acids – Membrane molecules • They are autocatalytic CSBRP-V3-Dec-2011
  27. 27. Free radical – induced cell injuryFree radical – induced cell injury • Injury by activated oxygen species • Free radical injury underlies 1. Chemical 2. Radiation 3. Toxicity from oxygen 4. Cellular aging 5. Microbial killing by phagocytes 6. Inflammatory cell damage 7. Tumor destruction by MØ CSBRP-V3-Dec-2011
  28. 28. NOTE: Production of free radicals in the cell:Production of free radicals in the cell: 1. due to insults (ex: chemical, radiation) 2. as a part of normal cellular activities CSBRP-V3-Dec-2011
  29. 29. Free radical – induced cell injuryFree radical – induced cell injury How they are produced with in the cells?How they are produced with in the cells? They are by products of normal cellThey are by products of normal cell metabolismmetabolism 1. Redox reactions [link] 2. Nitric oxide 3. Ionizing radiation 4. Enzymatic metabolism of some exogenous chemicals (ex: CCl4) CSBRP-V3-Dec-2011
  30. 30. Free radical – induced cell injuryFree radical – induced cell injury Important reactions that mediate cellImportant reactions that mediate cell injury by free radicals:injury by free radicals: • Lipid peroxidation of membranesLipid peroxidation of membranes • DNA fragmentationDNA fragmentation • Cross-linking of proteinsCross-linking of proteins CSBRP-V3-Dec-2011
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  33. 33. NOTE: Production of free radicals in the cell:Production of free radicals in the cell: 1. due to insults (ex: chemical, radiation) 2. as a part of normal cellular activities There are many intracellular mechanismsThere are many intracellular mechanisms that neutralize the normally produced freethat neutralize the normally produced free radicalsradicals CSBRP-V3-Dec-2011
  34. 34. Mechanisms to neutralize free radicalsMechanisms to neutralize free radicals produced normally with in the cells:produced normally with in the cells: • SODs • GSH / GSSH • Catalase • Anti-oxidants (Endogenous or exogenous) • Sequestration into other proteins CSBRP-V3-Dec-2011
  35. 35. Free radical – induced cell injuryFree radical – induced cell injury Natural NeutralizersNatural Neutralizers Superoxide radical O2 Hydrogen peroxide H2O2 OH SOD Catalase GSH/GSSH CSBRP-V3-Dec-2011
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  37. 37. Chemical injuryChemical injury CSBRP-V3-Dec-2011
  38. 38. Chemicals induce injury by any one of the two mechanisms: 1. Direct action (unaltered chemical) 2. Indirect action (altered chemical) Chemical injuryChemical injury CSBRP-V3-Dec-2011
  39. 39. 1. Direct action (unaltered chemical): They combine with a critical molecular component or cellular organelle Ex: HgCl2 (binding with –SH groups of various cell membrane proteins) Other examples: anti-neoplastic drugs antibiotics Chemical injuryChemical injury CSBRP-V3-Dec-2011
  40. 40. 1. Direct action (unaltered chemical): “The greatest damage occurs to those cells that use, absorb, excrete or concentrate the compound” Chemical injuryChemical injury CSBRP-V3-Dec-2011
  41. 41. 2. Indirect action (altered chemical): They are converted toxic metabolites Conversion occurs in the P450 of SER of liver Mechanism of injury: a- formation of reactive free radicals b- direct covalent binding to protein & lipids Ex: CCl4 and Acetaminophen Chemical injuryChemical injury CSBRP-V3-Dec-2011
  42. 42. 2. Indirect action (altered chemical): Action of CCl4 It’s converted in to toxic free radical CCl3 Cause lipid peroxidation, break down of ER In <30 min hepatic synthesis of proteins drops and in 2hrs swelling of SER and dissociation of ribosomes Fatty liver Mitochondrial injury – drop in ATP – cell swelling At the end Ca+ influx – activation of enzymes – cell death Chemical injuryChemical injury CSBRP-V3-Dec-2011
  43. 43. The answer is “No”“No” Injury of limited severity and short duration allows the cells to come back to their normal functional levels Survival of the cell to injury depends on its ability to respond and adapt to injury Are all injurious stimuli lethal?Are all injurious stimuli lethal? CSBRP-V3-Dec-2011
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  45. 45. Clinical scenariosClinical scenarios CSBRP-V3-Dec-2011
  46. 46. This is normal liver at medium power with zone 1 in periportal region, zone 2 in the middle of the lobule, and zone 3 in centrilobular region. A central vein and a portal triad define the lobule. CSBRP-V3-Dec-2011
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  52. 52. More examplesMore examples 1. Saccharin induced bladder cancer 2. Benzidine induced bladder cancer 3. Tx hyperthyroidism with radioactive iodine. 4. Anemia and DM 5. Hypoxic brain damage in severe anemia 6. Cystein given before radiation treatment for cancers 7. Antioxidants and longivityCSBRP-V3-Dec-2011
  53. 53. Which cell in the body thatWhich cell in the body that runs by anerobic glycolysisruns by anerobic glycolysis NORMALLY?NORMALLY? CSBRP-V3-Dec-2011
  54. 54. Response to injuryResponse to injury Depends on:Depends on: • Type of injury • Duration • Severity / extent • Consequences depend on 1. cell type 2. pre-existing state 3. adaptive response CSBRP-V3-Dec-2011
  55. 55. Response to injuryResponse to injury Can be:Can be: 1. Recovery 2. Adaptation 3. Apoptosis 4. Necrosis CSBRP-V3-Dec-2011
  56. 56. Adaptation:Adaptation: Alterations in cellular function / morphology to survive the insult Response to injuryResponse to injury CSBRP-V3-Dec-2011
  57. 57. AdaptationAdaptation Can be seen in twotwo situations: 1.1. PhysiologicalPhysiological adaptation 2.2. PathologicalPathological adaptation CSBRP-V3-Dec-2011
  58. 58. AdaptationAdaptation PhysiologicalPhysiological Adaptation to demand Ex:Ex: Enlargement of breast during puberty Enlargement of uterus during pregnancy Enlargement of biceps in iron pumpers PathologicalPathological Adaptation to injury in order to withstand the insult Ex:Ex: Wasting of muscle due to ischemia / disuse Increase in thickness of LV in HTN Osteopenia in bed ridden patients CSBRP-V3-Dec-2011
  59. 59. Cell adaptation to stressCell adaptation to stress Types of adaptations:Types of adaptations: 1. Hyperplasia 2. Hypertrophy 3. Atrophy 4. Metaplasia CSBRP-V3-Dec-2011
  60. 60. Cell adaptation to stressCell adaptation to stress Molecular mechanisms:Molecular mechanisms: Changes can occur at different levels 1. Receptors 2. Protein transcription 3. Switch of protein synthesis from one type to other CSBRP-V3-Dec-2011
  61. 61. HyperplasiaHyperplasia • Increase in the number of cells in an organ or tissue • Hence there is increase in volume of the organ or tissue • There is increased mitotic activity – >DNA synthesis • Usually it occurs with hypertrophy • Triggered by external stimuli • Hyperplasia can be physiological or pathological Ex: hormone induced growth of uterus CSBRP-V3-Dec-2011
  62. 62. Hyperplasia (HP)Hyperplasia (HP) • Physiological hyperplasia divided into 1-Hormonal HP 2-Compensatory HP 1-Hormonal HP: increases the functional capacity of the tissue Ex: Proliferation of glandular epithelium in breast at puberty, pregnancy Proliferation of smooth muscle of gravid uterus 2-Compensatory HP: increases tissue mass after damage / partial resection Ex: Capacity of the liver to regenerate unilateral nephrectomy with compensatory hyperplasia of contralateral kidney CSBRP-V3-Dec-2011
  63. 63. Prometheus chained to a mountain
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  65. 65. Pathological hyperplasiaPathological hyperplasia • Due to the action of GF or excessive hormonal stimulation on target cells • This proliferation is controlled – once the stimulus is removed, the proliferation regresses • This constitutes a fertile soil in which cancerous proliferations may occur CSBRP-V3-Dec-2011
  66. 66. Pathological hyperplasiaPathological hyperplasia Examples:Examples: EM hyperplasia – Estrogens Prostatic hyperplasia – Androgens Connective tissue hyperplasia – wound healing Warts – viral infections (HPV) CSBRP-V3-Dec-2011
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  68. 68. EM HyperplasiaEM Hyperplasia CSBRP-V3-Dec-2011
  69. 69. Prostatic HyperplasiaProstatic Hyperplasia CSBRP-V3-Dec-2011
  70. 70. HyperplasiaHyperplasia CSBRP-V3-Dec-2011
  71. 71. HypertrophyHypertrophy CSBRP-V3-Dec-2011
  72. 72. AtrophyAtrophy CSBRP-V3-Dec-2011
  73. 73. AtrophyAtrophy CSBRP-V3-Dec-2011
  74. 74. AtrophyAtrophy CSBRP-V3-Dec-2011
  75. 75. MetaplasiaMetaplasia CSBRP-V3-Dec-2011
  76. 76. Metaplasia in esophagusMetaplasia in esophagus CSBRP-V3-Dec-2011
  77. 77. E N D CSBRP-V3-Dec-2011
  78. 78. DysplasiaDysplasia CSBRP-V3-Dec-2011
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  86. 86. Dystrophic calcification • Any cell death • Tumor necrosis • Atheroma • Tuberculosis CSBRP-V3-Dec-2011
  87. 87. Intracellular accumulations • Endogenous a- Lipid (alcohol) b- Protein (alcohol, Alzheimer’s, Enzyme deficiencies) c- Glycogen (Enzyme deficiencies) d- Pigment (Lipofuchsin / melanin) • Exogenous pigment - hemosiderin CSBRP-V3-Dec-2011
  88. 88. Mechanisms of injuryMechanisms of injury 1.1. Mechanical disruption – TraumaMechanical disruption – Trauma 2. Failure of membrane integrity 3. Altered metabolic pathways 4. DNA damage 5. Deficiency of essential metabolites 6. Free radical generation CSBRP-V3-Dec-2011
  89. 89. Mechanisms of injuryMechanisms of injury 1. Mechanical disruption – Trauma 2.2. Failure of membrane integrityFailure of membrane integrity 3. Altered metabolic pathways 4. DNA damage 5. Deficiency of essential metabolites 6. Free radical generation CSBRP-V3-Dec-2011
  90. 90. Mechanisms of injuryMechanisms of injury Failure of membrane integrityFailure of membrane integrity • Compliment mediated cell lysis • Altered ion pumps & channels • Altered membrane lipids • Cross-linking membrane proteins • Altered calcium homeostsis • Lysosomal release CSBRP-V3-Dec-2011
  91. 91. Mechanisms of injuryMechanisms of injury 1. Mechanical disruption – Trauma 2. Failure of membrane integrity 3.3. Altered metabolic pathwaysAltered metabolic pathways 4. DNA damage 5. Deficiency of essential metabolites 6. Free radical generation CSBRP-V3-Dec-2011
  92. 92. Mechanisms of injuryMechanisms of injury Altered metabolic pathwaysAltered metabolic pathways • Cell respiration • Decreased protein systhesis • Depletion of ATP & active transport system CSBRP-V3-Dec-2011
  93. 93. Mechanisms of injuryMechanisms of injury 1. Mechanical disruption – Trauma 2. Failure of membrane integrity 3. Altered metabolic pathways 4.4. DNA damageDNA damage 5. Deficiency of essential metabolites 6. Free radical generation CSBRP-V3-Dec-2011
  94. 94. Mechanisms of injuryMechanisms of injury DNA damage / lossDNA damage / loss • Immediate consequences • Delayed consequences CSBRP-V3-Dec-2011
  95. 95. Mechanisms of injuryMechanisms of injury 1. Mechanical disruption – Trauma 2. Failure of membrane integrity 3. Altered metabolic pathways 4. DNA damage 5.5. Deficiency of essential metabolitesDeficiency of essential metabolites 6. Free radical generation CSBRP-V3-Dec-2011
  96. 96. Mechanisms of injuryMechanisms of injury Deficiency of essential metabolitesDeficiency of essential metabolites • Oxygen depletion (Link) • Glucose depletion • Hormone deficiency CSBRP-V3-Dec-2011
  97. 97. Mechanisms of injuryMechanisms of injury 1. Mechanical disruption – Trauma 2. Failure of membrane integrity 3. Altered metabolic pathways 4. DNA damage 5. Deficiency of essential metabolites 6.6. Free radical generationFree radical generation CSBRP-V3-Dec-2011
  98. 98. Mechanisms of injuryMechanisms of injury Free radical generationFree radical generation [link] Damaged lipids, proteins, DNA et.c. CSBRP-V3-Dec-2011
  99. 99. Mechanisms of injuryMechanisms of injury 1. Mechanical disruption – Trauma 2. Failure of membrane integrity 3. Altered metabolic pathways 4.4. DNA damageDNA damage 5. Deficiency of essential metabolites 6. Free radical generation CSBRP-V3-Dec-2011

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