Cell Injury And Cell Death (2006)(1)


Published on

Published in: Technology, Education
No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide
  • Normal cell has relative narrow range of functions and structure Limited changes in metabolism = homeostasis (increased Glc and TG metabolism in active contracting muscle) Stress = demands in excess of normal homeostatic changes leads to adaptations If stress exceeds adaptive response of cell -  injury In addition, a variety of agents can directly injure cells (ie CN, , Hg, pH, temp, etc)
  • Cell Injury And Cell Death (2006)(1)

    1. 1. Cell Injury and Cell Death Ashish kham budha magar
    2. 2. Adapted Cell + Stress Injury Normal cell Reversibly injured cell Irreversibly Injured cell Dead cell +Stress Apoptosis Necrosis - Stress - Stress Overview
    3. 5. Cell Adaptation, Injury and Death <ul><ul><li>Adaptation: In response to stimuli the cell develops a new altered state but remains functional (able to maintain homeostasis). </li></ul></ul><ul><ul><ul><li>Hyperplasia - ↑ cell # </li></ul></ul></ul><ul><ul><ul><li>Hypertrophy - ↑ cell mass </li></ul></ul></ul><ul><ul><ul><li>Atrophy - ↓ cell mass </li></ul></ul></ul><ul><ul><ul><li>Metaplasia – change from one adult form to another </li></ul></ul></ul>
    4. 6. Morphology of cell injury <ul><li>Swelling (via increased water content) </li></ul><ul><li>Fatty change (steatosis, TG) </li></ul><ul><li>Necrosis (dead cells) </li></ul><ul><li>Intracellular deposits (lipid, CHO, protein) </li></ul><ul><li>Loss of cellular fine structure (microvilli) </li></ul><ul><li>Karyolysis (DNA degradation) </li></ul><ul><li>Pyknosis (nuclear shrinkage) </li></ul><ul><li>Karyorrhexis (nuclear fragmentation) </li></ul>
    5. 7. Subcellular response to injury <ul><li>Lysosomes (heterophagy; autophagy) </li></ul><ul><li>Smooth ER (induction) </li></ul><ul><li>Mitochondria (  number, size and shape) </li></ul><ul><li>Cytoskeleton (  phagocytosis, locomotion) </li></ul><ul><li>Nucleus (karyolysis, karyorrhexis, pyknosis) </li></ul><ul><li>Membranes (cellular and subcellullar) </li></ul>
    6. 8. Causes of Cell Injury <ul><ul><li>O2 deprivation which impairs aerobic respiration & the ability to produce ATP. This is a common cause of cell death. </li></ul></ul><ul><ul><ul><li>a. Hypoxia- lack of O2 results in decreased aerobic respiration </li></ul></ul></ul><ul><ul><ul><li>b. Ischemia- lack of O2 & metabolic substrates </li></ul></ul></ul><ul><ul><li>Physical agents - mechanical trauma, temperature changes, shock, radiation etc. </li></ul></ul><ul><ul><li>Chemical agents & drugs - acids, bases, toxins, therapeutic drugs, pollutants, “social stimulants”, etc. </li></ul></ul>
    7. 9. Causes of Cell Injury <ul><li>4. Infectious agents </li></ul><ul><li>5. Immunologic reactions </li></ul><ul><ul><ul><ul><li>a. Xeno-immune reaction </li></ul></ul></ul></ul><ul><ul><ul><ul><li>b. Autoimmune reaction </li></ul></ul></ul></ul><ul><ul><ul><ul><li>c. “Normal“ immune response </li></ul></ul></ul></ul><ul><li>6. Genetic derangements </li></ul><ul><li>7. Nutritional imbalances </li></ul><ul><ul><ul><ul><li>a. Deficiencies </li></ul></ul></ul></ul><ul><ul><ul><ul><li>b. Excesses </li></ul></ul></ul></ul>
    8. 10. Mechanisms of cell injury <ul><li>3 Principles </li></ul><ul><li>The cellular response to injury depends on the type, duration and severity of the injury. </li></ul><ul><li>2. The consequences of the injury depend on the type, state and adaptability of the cell. </li></ul><ul><li>3. Cell injury results from an abnormality in one or more essential cellular components: </li></ul><ul><ul><li>Aerobic respiration (mitochondrial oxidation & ATP production) </li></ul></ul><ul><ul><li>Membrane integrity (cell & organelle membranes) </li></ul></ul><ul><ul><li>Protein synthesis </li></ul></ul><ul><ul><li>Cytoskeletal structure </li></ul></ul><ul><ul><li>The genetic apparatus </li></ul></ul>
    9. 11. Causes of Cell Injury <ul><li>Oxygen Deprivation </li></ul><ul><li>Physical Agents </li></ul><ul><li>Chemical Agents and Drugs </li></ul><ul><li>Infectious Agents </li></ul><ul><li>Immunologic Reactions </li></ul><ul><li>Genetic Derangements </li></ul><ul><li>Nutritional Imbalances </li></ul>
    10. 12. Physical Agents <ul><li>Mechanical trauma </li></ul><ul><li>Extremes of temperature – burns , deep cold </li></ul><ul><li>Radiation </li></ul><ul><li>Electric shock </li></ul>Causes of Cell Injury
    11. 13. Chemical Agents and Drugs <ul><li>Hypertonic concentration of salt – deranging electrolyte homeostasis </li></ul><ul><li>Poisons – arsenic, cyanide, or mercuric salts </li></ul><ul><li>Insecticides and Herbicides </li></ul><ul><li>Air pollutant – carbon monoxide </li></ul><ul><li>Occupational hazard – asbestos </li></ul><ul><li>Alcohol and Narcotic drugs </li></ul>Causes of Cell Injury
    12. 14. Infectious Agents <ul><li>Parasites </li></ul><ul><li>Fungi </li></ul><ul><li>Bacteria </li></ul><ul><li>Rickettsiae </li></ul><ul><li>Viruses </li></ul>Causes of Cell Injury
    13. 15. Immunologic Reactions <ul><li>Anaphylactic reaction to foreign protein or drug </li></ul><ul><li>Reactions to endogenous self-antigens – autoimmune diseases </li></ul>Causes of Cell Injury
    14. 16. Genetics Derangements <ul><li>Congenital malformation – Down syndrome </li></ul><ul><li>Decreased life of red blood cell – Thalassemia, Sickle cell anemia </li></ul><ul><li>Inborn errors of metabolism </li></ul>Causes of Cell Injury
    15. 17. Nutritional Imbalances <ul><li>Protein-calorie deficiencies </li></ul><ul><li>Vitamin deficiencies </li></ul><ul><li>Anorexia nervosa </li></ul><ul><li>Excesses of lipids – Obesity , Atherosclerosis </li></ul><ul><li>Metabolic diseases – Diabetes </li></ul>Causes of Cell Injury
    16. 18. Mechanisms of Cell Injury <ul><li>Depletion of ATP </li></ul><ul><li>Mitochondrial Damage </li></ul><ul><li>Influx of Intracellular Calcium and Loss of Calcium Homeostasis </li></ul><ul><li>Accumulation of Oxygen-Derived free radical ( Oxidative stress ) </li></ul><ul><li>Defects in Membrane Permeability </li></ul>
    17. 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
    18. 20. <ul><li>ATP depletion <5-10% of normal </li></ul><ul><ul><li>ATP use > ATP synthesis is a common consequence of both ischemic & toxic injury. </li></ul></ul><ul><ul><li>ATP production occurs via 2 related mechanism </li></ul></ul><ul><ul><ul><li>Glycolysis – cytosolic, low yield, lactate production (↓pH) </li></ul></ul></ul><ul><ul><ul><li>Oxidative phosphorylation – mitochondrial, high yield </li></ul></ul></ul><ul><ul><li>Hypoxia results in ↑ed glycolysis (depletion of glycogen & ↓pH) </li></ul></ul><ul><ul><li>ATP is critical for: </li></ul></ul><ul><ul><ul><li>Membrane transport </li></ul></ul></ul><ul><ul><ul><li>Maintenance of ionic gradients ( Na+, K+ Ca2+) </li></ul></ul></ul><ul><ul><ul><li>Protein synthesis </li></ul></ul></ul><ul><ul><ul><li>Cytoskeletal function (microfilaments) </li></ul></ul></ul>
    19. 21. Mechanisms of Cell Injury Depletion of ATP Na + K + Ca 2+
    20. 22. Mitochondrial Damage Mechanisms of Cell Injury Causes Hypoxia, Toxins Cytosolic Ca 2+ Oxidative stress Lipid breakdown product
    21. 23. Mitochondrial Damage Mechanisms of Cell Injury <ul><li>Mitochondrial permeability transition of inner membrane (formation of high-conductance channel ) </li></ul><ul><li>Leakage of Cytochrome c into cytosol </li></ul>ATP production Mitochondrial Oxidative Phosphorylation
    22. 24. <ul><li>Mitochondrial damage </li></ul><ul><ul><li>May occur directly due to hypoxia or increased Ca2+, oxidative stress or phospholipids breakdown. </li></ul></ul><ul><ul><li>Damage results in the formation of a high-conductance channel that dissipates the H+ ion gradient across the inner membrane (mitochondrial permeability transition (MPT)). Mitochondrial membrane damage can result in Cytochrome C leakage which can trigger apoptosis </li></ul></ul><ul><li>Defects in membrane permeability </li></ul><ul><ul><li>Membranes may be damaged directly by toxins, physical, chemical agents, activated complement components and perforins. </li></ul></ul><ul><ul><li>Increased cell membrane permeability disrupts intracellular osmolarity and enzyme activity </li></ul></ul><ul><ul><li>Organelle membrane defects cause organelle dysfunction and failure </li></ul></ul>
    23. 25. Mechanisms of Cell Injury Mitochondrial Damage
    24. 26. Influx of Intracellular Calcium and Loss of Calcium Homeostasis Mechanisms of Cell Injury
    25. 27. Mechanisms of Cell Injury
    26. 28. <ul><li>Accumulation of O2 derived free radicals </li></ul><ul><ul><li>Partially reduced, highly reactive, unstable oxygen moieties are able to: </li></ul></ul><ul><ul><ul><li>Induce the formation of more free radicals (propagation) </li></ul></ul></ul><ul><ul><ul><li>Damage lipids by peroxidation of double bonds resulting in breakage </li></ul></ul></ul><ul><ul><ul><li>Damage protein by oxidation and fragmentation </li></ul></ul></ul><ul><ul><ul><li>Damage nucleic acids ( chain breakage) </li></ul></ul></ul><ul><ul><li>Free radical formation occurs by </li></ul></ul><ul><ul><ul><li>Absorption of radiant energy (H2O -> O∙ + OH∙) </li></ul></ul></ul><ul><ul><ul><li>Metabolism of exogenous chemicals and drugs </li></ul></ul></ul><ul><ul><ul><li>Normal metabolic oxidation-reduction reactions (O2- , H2O2, OH∙) </li></ul></ul></ul><ul><ul><ul><li>Transition metals (Fe. Cu, etc.) can catalyze radical formation </li></ul></ul></ul><ul><ul><ul><li>Nitric oxide can act directly as a free radical or be converted to other highly reactive forms. </li></ul></ul></ul><ul><li>Free radical defense </li></ul><ul><ul><li>Free radicals are highly unstable and generally decay spontaneously </li></ul></ul><ul><ul><li>Antioxidants block the formation or scavenge them ( Vitamin E, C, A,; GSH) </li></ul></ul><ul><ul><li>Transition metals are usually tightly bound to carrier proteins (transferring, ferritin, lactoferin, ceruloplasmin); release and use are highly regulated. </li></ul></ul><ul><ul><li>Free radical scavenging systems defuse radicals rapidly </li></ul></ul><ul><ul><ul><li>Catalase </li></ul></ul></ul><ul><ul><ul><li>Glutathione oxidase </li></ul></ul></ul><ul><ul><ul><li>Superoxide dismutase </li></ul></ul></ul>
    27. 29. Free Radicals <ul><li>Free radicals </li></ul><ul><ul><li>Unstable oxygen species </li></ul></ul><ul><ul><li>Damage and break lipids, proteins and nucleic acids </li></ul></ul><ul><ul><li>Formed by normal metabolism. </li></ul></ul><ul><ul><li>Energy absorption </li></ul></ul><ul><ul><li>Metabolism of chemicals and drugs </li></ul></ul><ul><li>Free Radical Defense </li></ul><ul><ul><li>Spontaneous decay </li></ul></ul><ul><ul><li>Antioxidants </li></ul></ul><ul><ul><li>Free radical scavenging systems </li></ul></ul>
    28. 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
    29. 31. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) <ul><li>The Oxidation-Reduction reaction (normal metabolic processes) </li></ul><ul><li>-superoxide anion (O 2 - ) </li></ul><ul><li>-hydrogen peroxide (H 2 O 2 ) </li></ul><ul><li>-hydroxyl ion (OH ) </li></ul>Mechanisms of Cell Injury
    30. 32. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) <ul><li>Absorption of radiant energy (ultraviolet light: UV, X-ray) </li></ul>Mechanisms of Cell Injury H 2 0 Ionizing radiation OH H
    31. 33. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) <ul><li>Transition Metals – iron , copper </li></ul>Mechanisms of Cell Injury H 2 0 2 OH - Fe 3+ Fe 2+ “ Fenton reaction” OH
    32. 34. <ul><li>Lipid peroxidation of Membranes </li></ul><ul><li>- Plasma membrane </li></ul><ul><li>- Organellar membrane </li></ul>Effects of the free radicals on cell injury Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Mechanisms of Cell Injury Double bonds in unsaturated fatty acids membrane damage
    33. 35. <ul><li>Oxidative modification of proteins </li></ul><ul><li>- Oxidation of amino acid side chains </li></ul><ul><li>Protein-protein cross-linkages </li></ul><ul><li>- Oxidation of the protein backbone </li></ul><ul><li>Protein fragmentation </li></ul>Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Mechanisms of Cell Injury Effects of the free radicals
    34. 36. <ul><li>Lesions in DNA </li></ul><ul><li>Reaction with Thymine </li></ul><ul><li>DNA single-stranded break </li></ul><ul><li>DNA fragmentation </li></ul>Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) Mechanisms of Cell Injury Effects of the free radicals
    35. 37. Superoxide dismutase (SOD)
    36. 38. Defects in Membrane Permeability <ul><li>Mitochondrial Dysfunction </li></ul><ul><li>-Decreased phospholipid synthesis </li></ul><ul><li>-Phospholipase activation </li></ul><ul><li>Loss of Membrane phospholipid </li></ul>Mechanisms of Cell Injury Mechanism of Membrane damage in Cell Injury
    37. 39. <ul><li>Cytoskeletal Abnormality </li></ul><ul><li>Reactive Oxygen species </li></ul><ul><li>Lipid breakdown products </li></ul><ul><li>(detergen effect on membrane) </li></ul>Defects in Membrane Permeability Mechanisms of Cell Injury Mechanism of Membrane damage in Cell Injury Cytosolic Ca + protease
    38. 40. Cellular and biochemical sites of damage in cell injury
    39. 41. Cellular adaptation <ul><li>Hyperplasia: </li></ul><ul><ul><li>An organized increase in number of cells (versus: dysplasia, which is disorganized growth, and neoplasia, which is new growth). </li></ul></ul><ul><ul><li>Can be physiologic or pathologic </li></ul></ul><ul><li>Hypertrophy: </li></ul><ul><ul><li>An increase in cell size </li></ul></ul><ul><ul><li>Can be physiologic or pathologic </li></ul></ul>
    40. 42. Cellular adaptation (con’t) <ul><li>**Hyperplasia and hypertrophy can be difficult to separate--not possible by gross exam; difficult by microscopic exam. In some cases, both hyperplasia and hypertrophy occur together (e.g., breast and uterus during pregnancy). </li></ul><ul><li>Hyperplasia essentially does not occur in the brain and heart </li></ul>
    41. 43. Cellular adaptation (con’t) <ul><li>Atrophy: </li></ul><ul><ul><li>Decrease in cell size </li></ul></ul><ul><ul><li>Can be physiologic or pathologic </li></ul></ul><ul><li>Metaplasia: Change in type of epithelium (e.g., squamous epithelium to glandular epithelium) </li></ul>
    42. 44. Hyperplasia <ul><li>Physiologic: </li></ul><ul><ul><li>Breast enlargement during pregnancy (and hypertrophy) </li></ul></ul><ul><ul><li>Uterine enlargement during pregnancy (and hypertrophy) </li></ul></ul><ul><ul><li>Liver regrowth after partial resection </li></ul></ul><ul><ul><li>Inflammation, repair </li></ul></ul><ul><li>Pathologic: </li></ul><ul><ul><li>Ductal hyperplasia of breast (due to estrogen) </li></ul></ul><ul><ul><li>Benign prostatic hyperplasia </li></ul></ul><ul><ul><li>Endometrial hyperplasia (due to estrogen) </li></ul></ul><ul><ul><li>Viral infections </li></ul></ul><ul><ul><li>Endocrine organs with increased stimulus (e.g., adrenal gland enlargement due to ACTH-secreting pituitary adenoma; goiter) </li></ul></ul>
    43. 45. Hypertrophy <ul><li>Physiologic </li></ul><ul><ul><li>Skeletal muscle hypertrophy associated with exercise </li></ul></ul><ul><ul><li>Compensatory hypertrophy of kidney after removal of other kidney </li></ul></ul><ul><li>Pathologic </li></ul><ul><ul><li>Cardiac hypertrophy due to hypertension, valvular stenosis or insufficiency </li></ul></ul><ul><ul><li>Asthma--smooth muscle hypertrophy </li></ul></ul><ul><ul><li>Hypertrophy of bladder associated with prostatic gland hyperplasia </li></ul></ul>
    44. 46. Atrophy <ul><li>Physiologic </li></ul><ul><ul><li>Regression in size of breasts and uterus after pregnancy </li></ul></ul><ul><li>Pathologic </li></ul><ul><ul><li>Disuse (skeletal muscle atrophy) </li></ul></ul><ul><ul><li>Loss of endocrine stimulus (adrenal atrophy in patients on steroids) </li></ul></ul><ul><ul><li>Denervation (physical therapists vs forensic pathologists) </li></ul></ul><ul><ul><li>Inadequate nutrition </li></ul></ul><ul><ul><li>Ischemia (atrophy of kidney due to renal artery stenosis) </li></ul></ul>
    45. 47. Metaplasia <ul><li>Always pathologic </li></ul><ul><li>Examples: </li></ul><ul><ul><li>Squamous metaplasia of the lungs </li></ul></ul><ul><ul><li>Glandular metaplasia of the esophagus (Barrett esophagus) </li></ul></ul>
    46. 48. Cellular accumulations <ul><li>Lipofuscin </li></ul><ul><li>Calcium </li></ul><ul><li>Fat </li></ul><ul><li>Iron </li></ul><ul><li>Protein, cholesterol, glycogen </li></ul><ul><li>Pigments: </li></ul><ul><ul><li>Exogenous: Anthracosis, tattoos </li></ul></ul><ul><ul><li>Endogenous: Bile, melanin </li></ul></ul>
    47. 49. Why do cells accumulate substances? <ul><li>Too much produced </li></ul><ul><li>Too slow of clearance </li></ul><ul><ul><li>Lack of enzyme; decreased enzyme activity </li></ul></ul><ul><ul><li>Blockage of outlet </li></ul></ul><ul><li>Cellular accumulations are a sign of injury; cellular accumulations result from injury, or, their accumulation can cause cellular injury </li></ul>
    48. 50. Common locations of various cellular accumulations <ul><li>Lipofuscin (wear and tear pigment) </li></ul><ul><ul><li>Heart, liver </li></ul></ul><ul><li>Fat </li></ul><ul><ul><li>Liver, heart, kidney </li></ul></ul><ul><li>Iron </li></ul><ul><ul><li>Lung (in patients with congestive heart failure) </li></ul></ul><ul><ul><li>At site of past hemorrhage </li></ul></ul><ul><ul><li>In patients with hemochromatosis </li></ul></ul><ul><ul><ul><li>Liver, heart, pancreas </li></ul></ul></ul><ul><li>Cholesterol </li></ul>
    49. 51. Protein accumulation <ul><li>Alzheimer disease (tau protein) </li></ul><ul><li>Mallory hyaline (intermediate filaments; in alcoholic liver disease) </li></ul><ul><li>In kidney (as result of proteinuria) </li></ul>
    50. 52. Pigments <ul><li>Endogenous </li></ul><ul><ul><li>Bilirubin, melanin </li></ul></ul><ul><ul><li>Accumulation of bilirubin </li></ul></ul><ul><ul><ul><li>Too much produced (e.g., hemolysis) </li></ul></ul></ul><ul><ul><ul><li>Not processed (e.g., cirrhosis) </li></ul></ul></ul><ul><ul><ul><li>Outflow blocked (e.g. choledocholithiasis) </li></ul></ul></ul><ul><li>Exogenous </li></ul><ul><ul><li>Anthracosis (cigarette smoking; urban living) </li></ul></ul><ul><ul><li>Tattoo </li></ul></ul>
    51. 53. Calcification <ul><li>Dystrophic </li></ul><ul><ul><li>Patients have a normal calcium level </li></ul></ul><ul><ul><li>Calcification affects previously damaged tissue </li></ul></ul><ul><li>Metastatic </li></ul><ul><ul><li>Patients have an elevated level of calcium </li></ul></ul><ul><ul><ul><li>Causes: Hyperparathyroidism, bony metastases </li></ul></ul></ul><ul><ul><li>Calcification affects normal tissue and previously damaged tissue </li></ul></ul><ul><li>**Out of all forms of cellular adaptation, calcification is the only one which is not routinely reversible </li></ul>
    52. 54. Dysplasia <ul><li>Definition: Disorganized growth; hyperplasia leads to dysplasia which leads to neoplasia </li></ul><ul><li>Importance: Precursor of malignancy; but is reversible </li></ul><ul><li>Common locations: </li></ul><ul><ul><li>Cervix </li></ul></ul><ul><ul><li>Gastrointestinal tract </li></ul></ul><ul><li>Not commonly seen by forensic pathologists </li></ul>
    53. 55. Cellular adaptations commonly/uncommonly seen by forensic pathologists (biased) <ul><li>Hyperplasia </li></ul><ul><ul><li>Benign prostatic hyperplasia (uncommon) </li></ul></ul><ul><ul><li>Adrenal gland hyperplasia (common to uncommon) </li></ul></ul><ul><li>Hypertrophy </li></ul><ul><ul><li>Cardiac (common) </li></ul></ul><ul><li>Atrophy </li></ul><ul><li>Metaplasia </li></ul><ul><ul><li>Squamous metaplasia of lung and Barrett esophagus (uncommon) </li></ul></ul>
    54. 56. Cellular adaptations commonly/uncommonly seen by forensic pathologists (con’t) <ul><li>Fat </li></ul><ul><ul><li>Hepatic steatosis (common) </li></ul></ul><ul><li>Iron </li></ul><ul><ul><li>Congestive heart failure; sites of hemorrhage (common) </li></ul></ul><ul><ul><li>Hereditary hemochromatosis is rarely seen </li></ul></ul><ul><li>Protein accumulation </li></ul><ul><ul><li>Mallory hyaline (uncommon) </li></ul></ul><ul><ul><li>Tangles and plaques in Alzheimer dz (uncommon) </li></ul></ul><ul><li>Cholesterol </li></ul><ul><ul><li>Atherosclerosis (common) </li></ul></ul>
    55. 57. Cellular adaptations commonly/uncommonly seen by forensic pathologists <ul><li>Pigments </li></ul><ul><ul><li>Anthracosis (common) </li></ul></ul><ul><ul><li>Bile (uncommon) </li></ul></ul><ul><li>Calcification </li></ul><ul><ul><li>Atherosclerosis (common) </li></ul></ul><ul><ul><li>Aortic stenosis (uncommon) </li></ul></ul>
    56. 58. Morphology of Cell Injury and Necrosis <ul><li>Cell Injury – Reversible </li></ul><ul><li>– Irreversible </li></ul><ul><li>Cell Death – Necrosis </li></ul><ul><li>– Apoptosis </li></ul>
    57. 59. Morphology of Cell Injury <ul><li>Plasma membrane alteration </li></ul><ul><li>Mitochondrial Changes </li></ul><ul><li>Dilation of Endoplasmic reticulum </li></ul><ul><li>Nuclear Alteration </li></ul>Reversible Injury Cellular swelling Fatty change
    58. 60. Necrosis <ul><li>Coagulative </li></ul><ul><li>Liquefactive </li></ul><ul><li>Caseous </li></ul><ul><li>Fat </li></ul>
    59. 61. Reversible vs irreversible cell injury <ul><li>Reversible injury </li></ul><ul><li>* Decreased ATP levels </li></ul><ul><li>* Ion imbalance </li></ul><ul><li>* Swelling </li></ul><ul><li>Decreased pH </li></ul><ul><li>Fatty change (liver) </li></ul><ul><li>Irreversible injury </li></ul><ul><li>* Amorphous densities in mitochondria </li></ul><ul><li>* Severe membrane damage </li></ul><ul><li>* Lysosomal rupture </li></ul><ul><li>Extensive DNA damage </li></ul>
    60. 63. Morphology of Necrotic Cells <ul><li>Increased Eosinophilia </li></ul><ul><li>- loss of RNA (basophilia) </li></ul><ul><li>- denatured cytoplasmic protein </li></ul><ul><li>Nuclear Changes </li></ul><ul><li>- Pyknosis </li></ul><ul><li>- Karyorrhexis </li></ul><ul><li>- Karyolysis </li></ul><ul><li>Myelin figure </li></ul><ul><li>– large, whorled phospholipid mass (phospholipid precipitate) </li></ul>
    61. 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
    62. 66. Morphologic pattern of Necrotic Cell mass <ul><li>Coagulative necrosis </li></ul><ul><li>Liquefactive necrosis </li></ul><ul><li>Caseous necrosis </li></ul><ul><li>Fat necrosis </li></ul>
    63. 67. <ul><li>Coagulative Necrosis </li></ul><ul><li>:intracellular acidosis </li></ul><ul><li>– protein denatured </li></ul><ul><li>– proteolysis inhibited </li></ul>Morphologic pattern of Necrotic Cell mass
    64. 68. Coagulative necrosis <ul><li>Preservation of structure </li></ul><ul><li>Firm </li></ul><ul><li>Protein denaturation </li></ul><ul><li>Hypoxic tissue death (except brain) </li></ul>
    65. 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.
    66. 70. <ul><li>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. </li></ul>
    67. 71. Ischemic necrosis of the myocardium A, Normal myocardium. B, Myocardium with coagulation necrosis
    68. 72. <ul><li>Liquefactive Necrosis </li></ul><ul><li>:focal bacterial (or fungal) infections </li></ul><ul><li>– accumulation of inflammatory </li></ul><ul><li>cells </li></ul><ul><li>:hypoxic death of cells within CNS </li></ul>Morphologic pattern of Necrotic Cell mass
    69. 73. Liquefactive necrosis <ul><li>Enzymatic digestion </li></ul><ul><ul><li>Autolysis + WBC </li></ul></ul><ul><li>Liquid, viscous mass </li></ul><ul><li>May contain pus </li></ul><ul><li>Bacterial infections (via inflammation) </li></ul><ul><li>Hypoxic brain injury </li></ul>
    70. 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.
    71. 75. The liver shows a small abscess here filled with many neutrophils. This abscess is an example of localized liquefactive necrosis
    72. 76. <ul><li>Caseous necrosis </li></ul><ul><li>:gross appearance </li></ul><ul><li>:microscopic – granulomatous inflammation </li></ul>Morphologic Pattern of Necrotic Cell Mass
    73. 77. Caseous necrosis <ul><li>Subset of coagulative necrosis </li></ul><ul><li>TB </li></ul><ul><li>Cheesy, white </li></ul><ul><li>Surrounded by inflammatory cells (granulomatous reaction) </li></ul><ul><li>Complete destruction of tissue </li></ul>
    74. 78. A tuberculous lung with a large area of caseous necrosis
    75. 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
    76. 80. T uberculous granuloma showing an area of central necrosis, epithelioid cells, multiple Langhans-type giant cells, and lymphocytes.
    77. 81. Fat necrosis <ul><li>Not a specific pattern </li></ul><ul><li>Focal areas of fat digestion </li></ul><ul><li>Ususally via release of lipases from pancreas </li></ul><ul><li>FFA combine with Ca to produce “soaps” </li></ul>
    78. 82. Foci of fat necrosis with saponification in the mesentery
    79. 83. Ischemic injury
    80. 84. Mechanisms of Cell Injury Ischemic injury
    81. 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
    82. 86. Apoptosis <ul><li>Cell death that is induced by a tightly regulated intracellular program </li></ul><ul><li>“ Programmed Cell Death ” </li></ul><ul><li>Causes of Apoptosis </li></ul><ul><li>- Physiologic situations </li></ul><ul><li>- Pathologic conditions </li></ul>
    83. 87. Morphology of Apoptosis Cell shrinkage Chromosome condensation Formation of cytoplasmic blebs and apoptotic bodies Phagocytosis of apoptotic cells or cell bodies
    84. 88. Apoptosis in Physiologic Situations <ul><li>Programmed destruction of cell during embryogenesis </li></ul><ul><li>Hormone-dependent involution </li></ul><ul><li>- endometrial cells (menstrual cycle) </li></ul><ul><li>Cell deletion in proliferating cell population autoreactive T cells </li></ul><ul><li>Death of host cells - neutrophils </li></ul><ul><li>Elimination of self reactive lymphocyte </li></ul><ul><li>Cell death induced by cytotoxic T-cells </li></ul><ul><li>- viral infected or tumor cells </li></ul>
    85. 89. Apoptosis in Pathologic Conditions <ul><li>Cell death produced by injurious stimuli – radiation, cytotoxic drug </li></ul><ul><li>Cell injury in certain viral diseases – viral hepatitis </li></ul><ul><li>Pathologic atrophy </li></ul><ul><li>Cell death in tumors </li></ul>
    86. 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
    87. 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.
    88. 95. <ul><li>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 </li></ul>
    89. 97. <ul><li>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 </li></ul><ul><li>kinase activity. Both phosphorylate p53. </li></ul>
    90. 98. <ul><li>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 </li></ul><ul><li>integrins bind to thrombospondin. iii) phosphatidyl serine (annexin V) </li></ul>
    91. 99. <ul><li>Apoptosis can be suppressed </li></ul><ul><li>• at the level of caspases </li></ul><ul><li>• at the level of the mitochondria </li></ul><ul><li>• by ionic control </li></ul>
    92. 102. Intracellular Accumulations <ul><li>Manifestation of “ metabolic derangements” </li></ul><ul><li>: intracellular accumulation of abnormal amounts of various substances </li></ul><ul><li>Fat </li></ul><ul><li>Protein </li></ul><ul><li>Glycogen </li></ul><ul><li>Pigments </li></ul>
    93. 103. Mechanisms of intracellular accumulations <ul><li>abnormal metabolism </li></ul><ul><li>alterations in protein folding and transport </li></ul><ul><li>deficiency of critical enzymes </li></ul><ul><li>inability to degrade phagocytosed particles </li></ul>
    94. 104. Intracellular Accumulations of Lipids <ul><li>Accumulation of Lipids </li></ul><ul><li>- Triglycerides </li></ul><ul><li>- Cholesterol </li></ul><ul><li>Steatosis (fatty change) </li></ul><ul><li>: abnormal accumulation of triglycerides within parenchymal cells </li></ul><ul><li>– fatty liver in chronic alcoholism </li></ul>
    95. 105. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 October 2005 05:51 PM) © 2005 Elsevier Lipid circulation
    96. 106. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 October 2005 05:51 PM) © 2005 Elsevier Fatty liver
    97. 107. <ul><li>Cholesterol and Cholesterol Esters </li></ul><ul><li>: Atherosclerosis </li></ul><ul><li>- accumulation of cholesterol-laden macrophage ( foam cell ) and smooth muscle cells in the intima of aorta and arteries </li></ul><ul><li>: Cholesterolosis </li></ul><ul><li>- accumulation of foam cells in the lamina propria of gallbladder </li></ul>Intracellular Accumulations of Lipids
    98. 108. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 October 2005 05:51 PM) © 2005 Elsevier
    99. 109. <ul><li>Accumulation of protein droplets in proximal renal tubule </li></ul><ul><li>- renal disease with heavy protein leakage across the glomerular filter </li></ul>Intracellular Accumulations of Proteins
    100. 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
    101. 111. Intracellular Accumulations of Proteins <ul><li>Defects in protein folding </li></ul><ul><li>:Defective intracellular transport and secretion </li></ul><ul><li>:ER stress induced by unfolded and misfolded protein – cell death </li></ul><ul><li>:Aggregation of abnormal folded protein - amyloidosis </li></ul>
    102. 112. <ul><li>“ Patients with abnormal metabolism of glucose or glycogen” </li></ul><ul><li>Diabetes mellitus </li></ul><ul><li>:disorder of glucose metabolism </li></ul><ul><li>- glycogen accumulate in epithelial cells of renal tubules , liver cells , beta-cells of the islets of Langerhans and heart muscle cells </li></ul>Intracellular Accumulations of Glycogen
    103. 113. <ul><li>Glycogen storage disease (Glycogenosis) </li></ul><ul><li>- genetic diseases </li></ul><ul><li>- defect of enzymes in the synthesis or breakdown of glycogen </li></ul><ul><li>accumulation cell injury death </li></ul>Intracellular Accumulations of Glycogen
    104. 114. Accumulation of Pigments <ul><li>Exogenous pigments </li></ul><ul><li>Carbon ( anthracosis) </li></ul><ul><li>Coal dust ( pneumoconiosis) </li></ul><ul><li>Lung: pick up by alveolar macrophages regional lymph nods </li></ul><ul><li>blackening the tissues of the lungs </li></ul><ul><li>( anthracosis ) </li></ul>
    105. 115. <ul><li>Endogenous pigment </li></ul><ul><li>: Lipofuscin – aging pigment </li></ul><ul><li>lipid, phospholipid-protein complex (lipid peroxidation) </li></ul><ul><li>: Melanin – in melanocyte </li></ul><ul><li>: Hemosiderin – aggregates of ferritin micelles (iron + apoferritin = ferritin) </li></ul>Accumulation of Pigments
    106. 116. <ul><li>Abnormal tissue deposition of Calcium Salts </li></ul><ul><li>Two forms </li></ul><ul><li>1. Dystrophic calcification </li></ul><ul><li>2. Metastatic calcification </li></ul>Pathologic Calcification
    107. 117. Pathologic Calcification <ul><li>Dystrophic Calcification </li></ul><ul><li>- Area of tissue necrosis </li></ul><ul><li>- Aging or damage heart valve </li></ul><ul><li>- Atherosclerosis </li></ul><ul><li>- Single necrotic cell </li></ul><ul><li>“ psammoma body” </li></ul>
    108. 118. <ul><li>Metastatic Calcification </li></ul><ul><li>- Occur in normal tissue in “ hypercalcemia ” </li></ul>Pathologic Calcification <ul><li>Hypercalcemia </li></ul><ul><li>Hyperparathyroidism </li></ul><ul><li>Destruction of bone tissue </li></ul><ul><li>Renal failure </li></ul>
    109. 119. Cellular Response to Injury Nature & Severity of Injurious Stimuli Cellular Response <ul><li>Altered physiologic stimuli : </li></ul><ul><li>Increased demand, increased trophic stimulation (growth factors, hormones, work load, etc.) </li></ul><ul><li>Decreased nutrients, stimulation </li></ul><ul><li>Chronic irritation (chemical or physical) </li></ul><ul><li>Cellular Adaptation </li></ul><ul><li>Hyperplasia, hypertrophy </li></ul><ul><li>Atrophy </li></ul><ul><li>Metaplasia </li></ul><ul><li>Reduced O 2 supply; chemical injury; infection : </li></ul><ul><li>Acute, self limited </li></ul><ul><li>Progressive an severe (including DNA damage </li></ul><ul><li>. Mild chronic injury </li></ul><ul><li>Cell Injury </li></ul><ul><li>Acute reversible injury </li></ul><ul><li>Irreversible injury-> cell death </li></ul><ul><ul><li>Necrosis </li></ul></ul><ul><ul><li>Apoptosis </li></ul></ul><ul><li>Subcellular alterations in particular organelles </li></ul>Metabolic alterations, acquired or genetic <ul><li>Intercellular accumulations </li></ul><ul><li>proteins </li></ul><ul><li>lipids </li></ul><ul><li>carbohydrates </li></ul><ul><li>minerals </li></ul>Prolonged lifespan with cumulative sublethal injury Cellular aging
    110. 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
    111. 121. • Hypoxia - Oxygen deficiency • Ischemia - Impaired blood supply (arterial or venous occlusion) • Infarction - Area of necrosis due to ischemia
    112. 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)
    113. 123. FOUR VULNERABLE SYSTEMS: 􀀀• Cell membrane integrity 􀀀• ATP generation / mitochondrial function 􀀀• Protein synthesis / enzyme function 􀀀• Genetic integrity
    114. 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
    115. 125. Wake up