Chapter Two  adaptation and injury
Adaptation & Cellular Injury : <ul><li>Normal cell is in a steady state  “Homeostasis” </li></ul><ul><li>Cells constantly ...
Irreversible Injury   (cell death)   Reversible Injury   adaptation  normal   When cells encounter physiological stresses ...
adaptation <ul><li>A state that between normal, unstressed cell  and the injured, overstressed cell. </li></ul>
General principles <ul><li>1. The cellular response to injurious stimuli depends on the type of injury. </li></ul>
Incomplete occlusion of coronary artery  Complete or prolonged occlusion hypertesion Prolonged starvation
General principles <ul><li>2.The consequences of an injurious stimulus depend on the type, status, adaptability, and genet...
<ul><li>Skeletal muscle accommodates complete ischemia for 2 to 3 hours without irreversible injury. </li></ul><ul><li>car...
General principles <ul><li>3.Cellular function is far before cell death occurs, and the morphologic changes of cell injury...
 
General principles <ul><li>Cell membrane integrity, critical to cellular ionic and osmotic homeostasis; </li></ul><ul><li>...
 
 
 
 
General biochemical mechanisms <ul><li>Defects in plasma membrane permeability. </li></ul><ul><li>Oxygen deprivation or ge...
<ul><li>Cellular adaptation: </li></ul><ul><li>Atrophy </li></ul><ul><li>Hypertrophy </li></ul><ul><li>Hyperplasia </li></...
Types of adaptation
CELLULAR ADAPTATION <ul><li>Excessive physiologic stresses. </li></ul><ul><li>Some pathologic stimuli. </li></ul><ul><li>A...
<ul><li>ATROPHY </li></ul><ul><li>Decrease in mass of the cell </li></ul><ul><li>HYPERTROPHY  </li></ul><ul><li>Increase i...
ATROPHY  <ul><li>Inadequate nutrition. </li></ul><ul><li>Diminished blood supply. </li></ul><ul><li>Increased compression ...
Morphology of atrophy <ul><li>Brown atrophy </li></ul><ul><li>Reduction in the number of cell organelles. </li></ul><ul><l...
Fig 2-5
Cerebral atrophy - Alzheimers:
Atrophy of Brain <ul><li>The left part of the  brain diminishes in size.The gyrus is narrower and the gauge is widen. </li...
 
 
 
 
Hydropic change in ischemic - kidney Microvilli
Muscle ischemic atrophy:
 
 
 
 
Hydronephrosis
 
 
 
<ul><li>Hormonal hypertrophy  :  Specific hormonal stimulation   </li></ul><ul><li>Compensatory hypertrophy  :  Increased ...
Fig 2-6
 
 
Heart hypertrophy in hypertension: Left Ventricle
 
 
HYPERPLASIA
HYPERPLASIA <ul><li>Physiologic hyperplasia: </li></ul><ul><li>Hormonal hyperplasia </li></ul><ul><li>Compensatory hyperpl...
<ul><li>Fig 2-1 </li></ul>
PARTIAL HEPATECTOMY Priming Proliferation Growth lnhibition GROWTH FACTORS AND CYTOKINES HGF  TGF-  EGF TNF-  IL-6 Other...
 
 
Metaplasia <ul><li>One adult cell type is replaced by another. </li></ul><ul><li>Genetic reprogramming of stem cells. </li...
Intestinal glandular  epithelium <ul><li>Squamous metaplasia </li></ul><ul><li>Glandular metaplasia </li></ul><ul><li>Inte...
<ul><li>Connective tissue metaplasia </li></ul><ul><li>Bone metaplasia. </li></ul><ul><li>cartilige  metaplasia. </li></ul...
 
 
 
 
 
<ul><li>significance of metaplasia </li></ul><ul><li>A two-edged sword </li></ul><ul><li>An undesirable change </li></ul><...
<ul><li>Cell  injury </li></ul>Section B
Causes of cell injury and disease <ul><li>Oxygen deprivation ( hypoxia, ischemia) </li></ul><ul><li>Nutritional imbalances...
 
HYPOXIA <ul><li>Ischemia ( loss of blood supply ). </li></ul><ul><li>Inadequate oxygenation </li></ul><ul><li>( cardioresp...
HYPOXIC INJURY <ul><li>Loss of oxidative phosphorylation and ATP generation by mitochondria. </li></ul><ul><li>Decreased A...
Four biochemical themes <ul><li>Oxygen-derived free radicals. </li></ul><ul><li>Loss of calcium homeostasis and increased ...
PHYSICAL AGENTS <ul><li>Trauma </li></ul><ul><li>Heat </li></ul><ul><li>Cold </li></ul><ul><li>Radiation </li></ul><ul><li...
CHEMICAL AGENTS AND DRUGS <ul><li>Endogenous products: urea </li></ul><ul><li>Exogenous agents: </li></ul><ul><li>Therapeu...
MECHANISMS OF CHEMICAL INJURY <ul><li>Directly:  Mercury of mercuric chloride binds to SH groups of cell membrane proteins...
<ul><li>By conversion to reactive toxic metabolites which in turn cause cell injury either by direct covalent binding to m...
<ul><li>CCl 4  in SER of liver cell (P-450) – CCl 3 .  – lipid peroxidation and autocatalytic reactions – swelling and bre...
FREE RADICAL INITIATION <ul><li>Absorption of energy (UV light and x-rays) </li></ul><ul><li>Oxidative metabolic reactions...
Cell injury caused by free radicals through <ul><li>Peroxidation of lipids. </li></ul><ul><li>Cross linking proteins by th...
INFECTIOUS AGENTS <ul><li>Viruses </li></ul><ul><li>Rickettsiae </li></ul><ul><li>Bacteria </li></ul><ul><li>Fungi </li></...
<ul><li>Marfan syndrome </li></ul><ul><li>Fibrillin, a scaffolding on which tropoelastin   is deposited to form  elastic f...
<ul><li>Adenomatous polyposis coli </li></ul><ul><li>APC loci, 5q21 </li></ul><ul><li>Adenomatous polyposis in colons (in ...
CELLS REACT TO ADVERSE INFLUENCES <ul><li>ADAPTING </li></ul><ul><li>SUSTAINING REVERSIBLE INJURY </li></ul><ul><li>SUFFER...
CELL INJURY AND NECROSIS <ul><li>General mechanisms: </li></ul><ul><li>Maintenance of the integrity of cell membranes.  </...
 
Irreversible Injury   Reversible Injury   adaptation   normal
Types of cell injury  <ul><li>reversible </li></ul><ul><li>irreversible </li></ul>necrosis apoptosis
Reversible injury <ul><li>Cellular swelling </li></ul><ul><li>Fatty change </li></ul><ul><li>Hyaline change </li></ul>
Cellular swelling
 
<ul><li>Excessive entry of free fatty acids into the liver </li></ul><ul><li>(starvation, corticosteroid therapy). </li></...
<ul><li>Morphology of fatty change </li></ul><ul><li>Sudan III, Oil red O, Osmic acid </li></ul><ul><li>Liver </li></ul><u...
 
 
<ul><li>Intracellular hyaline changes </li></ul><ul><li>Hyaline degeneration of arterioles </li></ul><ul><li>Hyaline degen...
<ul><li>Absorption of protein causing hyaline  </li></ul><ul><li>droplets in proximal epithelial cells in </li></ul><ul><l...
 
 
 
 
Hyaline change of the central artery of the spleen (spleen of hypertension disease) <ul><li>The narrowing of the lumina wi...
<ul><li>Mucoid Degeneration </li></ul><ul><li>mucopolysaccharide deposition in the stroma of connective tissue. </li></ul>
mucoid degeneration
<ul><li>A heterogeneous group of pathogenic  </li></ul><ul><li>fibrillar proteins accumulating in tissues </li></ul><ul><l...
 
Chemical nature of amyloid fibrils Two major forms: AL (amyloid light chain protein) AA (amyloid-associated protein):   De...
Minor forms of amyloid fibrils: Transthyretin (TTR): A mutant form of a  serum protein in familial amyloid  polyneuropathy...
Minor forms of amyloid fibrils:   Beta-2-amyloid protein forms the core of  cerebral plaques and deposits within  cerebral...
Minor forms of amyloid fibrils: Transthyretin (TTR): A mutant form of a  serum protein in familial amyloid  polyneuropathy...
Minor forms of amyloid fibrils:   Beta-2-amyloid protein forms the core of  cerebral plaques and deposits within  cerebral...
<ul><li>primary (B-cell dyscrasia, AL) </li></ul><ul><li>Secondary or reactive (AA):  </li></ul><ul><li>Collagen diseases,...
<ul><li>Nodular (tumor-forming deposits,  </li></ul><ul><li>B-cell dyscrasia, AL)  </li></ul><ul><li>Endocrine amyloidosis...
 
<ul><li>Exogenous:   </li></ul><ul><li>Carbon </li></ul><ul><li>Tattooing </li></ul><ul><li>Endogenous: </li></ul><ul><li>...
 
 
 
 
 
 
<ul><li>Dystrophic calcification </li></ul><ul><li>Metastatic calcification </li></ul>Pathologic calcification
<ul><li>Necrotic tissues </li></ul><ul><li>Atheroma </li></ul><ul><li>Damaged heart valves </li></ul>Dystrophic calcificat...
<ul><li>Fig 2-13 </li></ul>
 
<ul><li>Increased secretion of parathyroid  </li></ul><ul><li>hormone </li></ul><ul><li>Destruction of bone tissue </li></...
Metastatic calcification Affecting Interstitial tissue of gastric mucosa Kidneys Lungs Pulmonary veins  Systemic arteries
Section C CELL DEATH
TYPES OF CELL DEATH <ul><li>necrosis </li></ul><ul><li>Coagulation necrosis </li></ul><ul><li>Caseous necrosis </li></ul><...
<ul><li>Swelling, denaturation and coagulation  </li></ul><ul><li>of proteins </li></ul><ul><li>Breakdown of cellular orga...
NECROSIS The sum of the morphologic changes that follow cell death in living tissue and organ: <ul><li>Denaturation of pro...
<ul><li>Enzymatic digestion by lysosomal enzymes of the dead cells themselves. </li></ul>AUTOLYSIS HETEROLYSIS <ul><li>Dig...
<ul><li>Nucleus changes : </li></ul><ul><li>The hallmarks of cell death in three patterns: </li></ul><ul><li>Basic Patholo...
1)Three pattern of nuclear changes Karyolysis (DNase activity) Pyknosis (DNA condensation) Karyorrhexis (fragmentation of ...
<ul><li>Pyknosis : nuclear shrinkage and increased basophilia, and the DNA apparently condenses into a solid, shrunken bas...
 
<ul><li>Cytoplasm change:   </li></ul><ul><li>increased eosinophilium and a more glassy homogeneous appearance and even va...
<ul><li>Types of Necrosis </li></ul>Coagulative Necrosis Liquefactive Necrosis Fibrinoid Necrosis Necrosis Gangrenous Necr...
Morphologic appearance of necrosis <ul><li>Increased eosinophilia: </li></ul><ul><li>Loss of RNA in the cytoplasm  </li></...
Coagulation necrosis Denatures of both structural and  enzymatic proteins by injury or the  subsequent increasing intracel...
Renal Infarction - Coagulative
Splenic Infarction - Coagulative necrosis
Infarction -  Adrenal gland:
 
Caseous necrosis A subtype of coagulation necrosis White and cheesy Tuberculosis Completely obliterated tissue  architecture
Caseous necrosis of kidney <ul><li>The necrosis area is soft, white-yellow cheesy appearance. </li></ul>
 
Extensive  Caseous necrosis Tuberculosis
 
<ul><li>Liquefactive necrosis </li></ul><ul><li>Bacterial or fungal infections </li></ul><ul><li>Central nervous system </...
Liver abscess: Liquifactive necrosis
Stroke- Liquifactive necrosis
 
 
<ul><li>Fat necrosis </li></ul><ul><li>Traumatic </li></ul><ul><li>Activated pancreatic lipases </li></ul>
Fat necrosis(Steatonecrosis) <ul><li>Only shadowy outlines of necrotic fat cells may be seen, with basophilic calcium depo...
<ul><li>Fibrinoid degeneration Deeply eosinophilic </li></ul><ul><li>Collagen diseases </li></ul><ul><li>Necrotic vasculit...
Fibrinoid Necrosis <ul><li>homogeneous, deeply eosinophilic in necrosis. </li></ul>
<ul><li>Gangrene </li></ul><ul><li>A subtype of coagulation necrosis </li></ul><ul><li>Dry gangrene </li></ul><ul><li>Wet ...
Caseous necrosis - Tuberculosis
Gangrene - Amputated Diabetic foot
 
 
Gangrene Intestine - Thrombosis.
 
<ul><li>Absorption </li></ul><ul><li>Discharge: Erosion  Ulcer </li></ul><ul><li>Sinus  Fistula  Cavitation </li></ul><ul>...
 
 
 
 
 
 
Section D APOPTOSIS
APOPTOSIS  (Programmed cell death)   <ul><li>Programmed destruction of cells during  </li></ul><ul><li>embryogenesis. </li...
<ul><li>Pathologic atrophy in parenchymal  </li></ul><ul><li>organs after duct obstruction. </li></ul><ul><li>Cell death b...
MORPHOLOGICAL FEATURES OF APOPTOSIS <ul><li>Cell shrinkage </li></ul><ul><li>Chromatin condensation and fragmentation. </l...
Necrosis   Apoptosis Stimuli   Hypoxia  Physical Toxins  Pathological Histology   Cell swelling  Single cell  Coagulation ...
Necrosis   Apoptosis Mechanism  ATP depletion  Gene activation Membrane  Endonuclease injury Free radicals Tissue  Inflamm...
<ul><li>Fig 1-18 </li></ul>
 
Biochemical features of apoptosis 1.PROTEIN CLEAVAGE:   Caspases (cysteine protease) Nuclear scaffold Cytoskeletal protein...
3. DNA breakdown:   50-300 kb pieces Ca2+, Mg2+ dependent endonucleases DNA oligonucleosomes DNA ladders (also seen in nec...
<ul><li>Fig 1-19 </li></ul>
<ul><li>Apoptosis-associated genes </li></ul><ul><li>bcl-2, c-myc, p53 </li></ul>
<ul><li>Fig 1-20 </li></ul>
<ul><li>Occuring conditions </li></ul><ul><li>during embryogenesis and development; </li></ul><ul><li>as a homeostatic mec...
<ul><li>Morphologic features   </li></ul><ul><li>Cell shrinkage.  </li></ul><ul><li>Chromatin condensation </li></ul><ul><...
<ul><li>A specific biochemical feature </li></ul><ul><li>breakdown of DNA into large 180 to 200-kilobase pieces, by Ca 2+ ...
normalcell Cellular swelling, chromatin cluping Membrane damage Nuclear chromatin condensation and fragmentation Cytoplasm...
Apotosis of hepatocytes
Comparison of cell death by apoptosis and necrosis
Terminology: <ul><li>Necrosis:  Morphologic changes seen in dead cells within living tissue. </li></ul><ul><li>Autolysis: ...
Types of Necrosis: <ul><li>Coagulative – Eg. Infarction </li></ul><ul><li>Liquifactive - Brain, abscess </li></ul><ul><li>...
Ageing: <ul><li>“ Progressive time related loss of structural and functional capacity of cells leading to death” </li></ul...
Factors affecting Ageing: <ul><li>Genetic – Clock genes,  (fibroblasts) </li></ul><ul><li>Diet – malnutrition, obesity etc...
Cellular mechanisms of ageing <ul><li>Cross linking proteins & DNA. </li></ul><ul><li>Accumulation of toxic by-products. <...
Telomerase in ageing: Germ Cells Somatic Cells
Ageing –changes: <ul><li>Gradual atrophy of tissues and organs. </li></ul><ul><li>Dementia </li></ul><ul><li>Loss of skin ...
Pathology of elderly
Factors affecting ageing: <ul><li>Stress </li></ul><ul><li>Infections </li></ul><ul><li>Diseases </li></ul><ul><li>Malnutr...
Conclusions: <ul><li>Cellular Injury - Various causes </li></ul><ul><li>Reversible Injury    Adaptations </li></ul><ul><u...
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Tissue Injury

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  • Tissue Injury

    1. 1. Chapter Two adaptation and injury
    2. 2. Adaptation & Cellular Injury : <ul><li>Normal cell is in a steady state “Homeostasis” </li></ul><ul><li>Cells constantly adjust structure and function to accommodate changing demands and extracellular stress. </li></ul><ul><li>But within a relatively narrow range of physiologic parameter. </li></ul><ul><li>Change in Homeostasis due to stimuli - Injury </li></ul>
    3. 3. Irreversible Injury (cell death) Reversible Injury adaptation normal When cells encounter physiological stresses or pathological stimuli, they undergo adaptation, achieving a new a steady state and preserving viability. If the adaptive capacity is exceeded, cell injury develops. Within certain limits, injury is reversible. with severe and persistent stress, irreversible injury results.
    4. 4. adaptation <ul><li>A state that between normal, unstressed cell and the injured, overstressed cell. </li></ul>
    5. 5. General principles <ul><li>1. The cellular response to injurious stimuli depends on the type of injury. </li></ul>
    6. 6. Incomplete occlusion of coronary artery Complete or prolonged occlusion hypertesion Prolonged starvation
    7. 7. General principles <ul><li>2.The consequences of an injurious stimulus depend on the type, status, adaptability, and genetic makeup of injured cell. </li></ul>
    8. 8. <ul><li>Skeletal muscle accommodates complete ischemia for 2 to 3 hours without irreversible injury. </li></ul><ul><li>cardiac muscle dies after 20 to 30 minutes. </li></ul><ul><li>Neuron dies after a few minutes. </li></ul>
    9. 9. General principles <ul><li>3.Cellular function is far before cell death occurs, and the morphologic changes of cell injury(or death) lag far behind both. </li></ul>
    10. 11. General principles <ul><li>Cell membrane integrity, critical to cellular ionic and osmotic homeostasis; </li></ul><ul><li>ATP generation, largely via mitochondrial aerobic respiration; </li></ul><ul><li>Protein synthesis; </li></ul><ul><li>Intergrity of the genetic apparatus. </li></ul>4. four intracellular systems are particularly vulnerable.
    11. 16. General biochemical mechanisms <ul><li>Defects in plasma membrane permeability. </li></ul><ul><li>Oxygen deprivation or generation of reactive oxygen species(free radical). </li></ul><ul><li>Loss of calcium homeostasis. </li></ul><ul><li>Mitochondrial damage. </li></ul><ul><li>Chemical injury </li></ul><ul><li>Genetic variation </li></ul>
    12. 17. <ul><li>Cellular adaptation: </li></ul><ul><li>Atrophy </li></ul><ul><li>Hypertrophy </li></ul><ul><li>Hyperplasia </li></ul><ul><li>Metaplasia </li></ul>Section A
    13. 18. Types of adaptation
    14. 19. CELLULAR ADAPTATION <ul><li>Excessive physiologic stresses. </li></ul><ul><li>Some pathologic stimuli. </li></ul><ul><li>A new, but altered state preserving </li></ul><ul><li>the viability of the cell. </li></ul>
    15. 20. <ul><li>ATROPHY </li></ul><ul><li>Decrease in mass of the cell </li></ul><ul><li>HYPERTROPHY </li></ul><ul><li>Increase in mass of the cell </li></ul>
    16. 21. ATROPHY <ul><li>Inadequate nutrition. </li></ul><ul><li>Diminished blood supply. </li></ul><ul><li>Increased compression </li></ul><ul><li>Loss of innervation. </li></ul><ul><li>Decreased workload </li></ul><ul><li>Loss of endocrine stimulation. </li></ul><ul><li>Aging </li></ul>malnutrational Denervative endocrine Disuse compressive Aging
    17. 22. Morphology of atrophy <ul><li>Brown atrophy </li></ul><ul><li>Reduction in the number of cell organelles. </li></ul><ul><li>Increase in the number of autophagic vacuoles. </li></ul><ul><li>Lipofuscin granules (Brown atrophy) </li></ul>
    18. 23. Fig 2-5
    19. 24. Cerebral atrophy - Alzheimers:
    20. 25. Atrophy of Brain <ul><li>The left part of the brain diminishes in size.The gyrus is narrower and the gauge is widen. </li></ul>
    21. 30. Hydropic change in ischemic - kidney Microvilli
    22. 31. Muscle ischemic atrophy:
    23. 36. Hydronephrosis
    24. 40. <ul><li>Hormonal hypertrophy : Specific hormonal stimulation </li></ul><ul><li>Compensatory hypertrophy : Increased functional demand </li></ul>HYPERTROPHY
    25. 41. Fig 2-6
    26. 44. Heart hypertrophy in hypertension: Left Ventricle
    27. 47. HYPERPLASIA
    28. 48. HYPERPLASIA <ul><li>Physiologic hyperplasia: </li></ul><ul><li>Hormonal hyperplasia </li></ul><ul><li>Compensatory hyperplasia </li></ul><ul><li>Pathologic hyperplasia: </li></ul><ul><li>Excessive hormonal stimulation. </li></ul><ul><li>Effects of locally produced GFs on target cells. </li></ul>female breast and uterus at puberty and pregnancy.
    29. 49. <ul><li>Fig 2-1 </li></ul>
    30. 50. PARTIAL HEPATECTOMY Priming Proliferation Growth lnhibition GROWTH FACTORS AND CYTOKINES HGF TGF-  EGF TNF-  IL-6 Others ADJUVANTS Norepinephrine Insulin Glucagon Thyroid hormone GROWTH INHIBITORS TGF-  Others Growth factors Adjuvanis Matrix degradation
    31. 53. Metaplasia <ul><li>One adult cell type is replaced by another. </li></ul><ul><li>Genetic reprogramming of stem cells. </li></ul><ul><li>Epithelial and mesenchymal metaplasia. </li></ul>
    32. 54. Intestinal glandular epithelium <ul><li>Squamous metaplasia </li></ul><ul><li>Glandular metaplasia </li></ul><ul><li>Intestinal metaplasia of gastric epithelia </li></ul>Bronchial epithelia Epithelia in bile duct Cervical epithelia Epithelial metaplasia Columnar epithelium Squamous epithelium Squamous epithelium Gastric glandular epithelium Barrett esophagitis
    33. 55. <ul><li>Connective tissue metaplasia </li></ul><ul><li>Bone metaplasia. </li></ul><ul><li>cartilige metaplasia. </li></ul><ul><li>Inmatured fibroblasts </li></ul>Osteocytes Chondrocytes mesenchymal metaplasia
    34. 61. <ul><li>significance of metaplasia </li></ul><ul><li>A two-edged sword </li></ul><ul><li>An undesirable change </li></ul><ul><li>Survive but some important protective mechanism is lost. </li></ul><ul><li>The influences that predispose to such squamous metaplasia, if persistent, may promote cancer transformation in metaplastic epithelium. </li></ul>
    35. 62. <ul><li>Cell injury </li></ul>Section B
    36. 63. Causes of cell injury and disease <ul><li>Oxygen deprivation ( hypoxia, ischemia) </li></ul><ul><li>Nutritional imbalances </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>
    37. 65. HYPOXIA <ul><li>Ischemia ( loss of blood supply ). </li></ul><ul><li>Inadequate oxygenation </li></ul><ul><li>( cardiorespiratory failure ). </li></ul><ul><li>Loss of oxygen-carrying capacity of the blood ( anemia or CO poisoning ). </li></ul>
    38. 66. HYPOXIC INJURY <ul><li>Loss of oxidative phosphorylation and ATP generation by mitochondria. </li></ul><ul><li>Decreased ATP (with increase in AMP): stimulating fructokinase and phosphorylation, resulting in aerobic glycolysis. </li></ul><ul><li>Depleted glycogen. </li></ul><ul><li>Reduced intracellular pH: Lactic acid and inorganic phosphate. </li></ul><ul><li>Clumping of nuclear chromatin. </li></ul>
    39. 67. Four biochemical themes <ul><li>Oxygen-derived free radicals. </li></ul><ul><li>Loss of calcium homeostasis and increased intracellular calcium. </li></ul><ul><li>ATP depletion. </li></ul><ul><li>Defects in membrane permeability. </li></ul>
    40. 68. PHYSICAL AGENTS <ul><li>Trauma </li></ul><ul><li>Heat </li></ul><ul><li>Cold </li></ul><ul><li>Radiation </li></ul><ul><li>Electric shock </li></ul>
    41. 69. CHEMICAL AGENTS AND DRUGS <ul><li>Endogenous products: urea </li></ul><ul><li>Exogenous agents: </li></ul><ul><li>Therapeutic drugs: hormones </li></ul><ul><li>Nontherapeutic agents: </li></ul><ul><li>lead or alcohol </li></ul>
    42. 70. MECHANISMS OF CHEMICAL INJURY <ul><li>Directly: Mercury of mercuric chloride binds to SH groups of cell membrane proteins, causing increased permeability and inhibition of ATPase-dependent transport. </li></ul>
    43. 71. <ul><li>By conversion to reactive toxic metabolites which in turn cause cell injury either by direct covalent binding to membrane protein and lipid, or more commonly by the formation of free radicals. </li></ul>MECHANISMS OF CHEMICAL INJURY
    44. 72. <ul><li>CCl 4 in SER of liver cell (P-450) – CCl 3 . – lipid peroxidation and autocatalytic reactions – swelling and breakdown of ER, dissociation of ribosome, and decreased hepatic protein synthesis ( loss of lipid acceptor protein – fatty change of liver cell) – progressive cellular swelling, plasma membrane damage, and cell death. </li></ul>
    45. 73. FREE RADICAL INITIATION <ul><li>Absorption of energy (UV light and x-rays) </li></ul><ul><li>Oxidative metabolic reactions </li></ul><ul><li>Enzymatic conversion of exogenous chemicals or drugs (CCl 4 >CCl 3 . ) </li></ul><ul><li>Oxygen-derived radicals </li></ul><ul><li>Superoxide </li></ul>
    46. 74. Cell injury caused by free radicals through <ul><li>Peroxidation of lipids. </li></ul><ul><li>Cross linking proteins by the formation of disulfide bonds. </li></ul><ul><li>Induction of DNA damage that has been implicated both in cell killing and malignant transformation. </li></ul>
    47. 75. INFECTIOUS AGENTS <ul><li>Viruses </li></ul><ul><li>Rickettsiae </li></ul><ul><li>Bacteria </li></ul><ul><li>Fungi </li></ul><ul><li>Parasites </li></ul>
    48. 76. <ul><li>Marfan syndrome </li></ul><ul><li>Fibrillin, a scaffolding on which tropoelastin is deposited to form elastic fibers. </li></ul><ul><li>FBN1, 15q21, mutations in Marfan syndrome. </li></ul><ul><li>FBN2, 5q3, mutations in congenital contractual arachnodactyly. </li></ul><ul><ul><ul><ul><li>Genetic derangements </li></ul></ul></ul></ul>
    49. 77. <ul><li>Adenomatous polyposis coli </li></ul><ul><li>APC loci, 5q21 </li></ul><ul><li>Adenomatous polyposis in colons (in teens). </li></ul><ul><li>100% malignant transformation (  40ys ). </li></ul><ul><li>APC protein in the cytoplasm. </li></ul><ul><li>Several partners, including  -catenin. </li></ul><ul><li> -catenin  entering the nucleus  activating transcription of growth-promoting genes. </li></ul><ul><li>Causing degradation of  -catenin  maintaining </li></ul><ul><li>low level of  -catenin in the cytoplasm. </li></ul>
    50. 78. CELLS REACT TO ADVERSE INFLUENCES <ul><li>ADAPTING </li></ul><ul><li>SUSTAINING REVERSIBLE INJURY </li></ul><ul><li>SUFFERING IRREVERSIBLE INJURY AND DYING </li></ul>
    51. 79. CELL INJURY AND NECROSIS <ul><li>General mechanisms: </li></ul><ul><li>Maintenance of the integrity of cell membranes. </li></ul><ul><li>Aerobic respiration and production of ATP. </li></ul><ul><li>Synthesis of enzymes and structure proteins. </li></ul><ul><li>Preservation of the integrity of the genetic apparatus. </li></ul>
    52. 81. Irreversible Injury Reversible Injury adaptation normal
    53. 82. Types of cell injury <ul><li>reversible </li></ul><ul><li>irreversible </li></ul>necrosis apoptosis
    54. 83. Reversible injury <ul><li>Cellular swelling </li></ul><ul><li>Fatty change </li></ul><ul><li>Hyaline change </li></ul>
    55. 84. Cellular swelling
    56. 86. <ul><li>Excessive entry of free fatty acids into the liver </li></ul><ul><li>(starvation, corticosteroid therapy). </li></ul><ul><li>Enhanced fatty acid synthesis. </li></ul><ul><li>Decreased fatty acid oxidation. </li></ul><ul><li>Increased esterification of fatty acid to </li></ul><ul><li>triglycerides (alcohol). </li></ul><ul><li>Decreased apoprotein synthesis (CCl 4 ). </li></ul><ul><li>Impaired lipoprotein secretion from the liver </li></ul><ul><li>(alcohol). </li></ul>FATTY CHANGE
    57. 87. <ul><li>Morphology of fatty change </li></ul><ul><li>Sudan III, Oil red O, Osmic acid </li></ul><ul><li>Liver </li></ul><ul><li>Heart </li></ul><ul><li>Kidney </li></ul>
    58. 90. <ul><li>Intracellular hyaline changes </li></ul><ul><li>Hyaline degeneration of arterioles </li></ul><ul><li>Hyaline degeneration of connective tissue </li></ul>Hyaline changes (degeneration)
    59. 91. <ul><li>Absorption of protein causing hyaline </li></ul><ul><li>droplets in proximal epithelial cells in </li></ul><ul><li>the kidney. </li></ul><ul><li>Russel bodies in plasma cells. </li></ul><ul><li>Viral inclusions in the cytoplasm or </li></ul><ul><li>the nucleus. </li></ul><ul><li>Masses of altered intermediate filaments </li></ul><ul><li>(Mallory bodies). </li></ul>Intracellular hyaline changes
    60. 96. Hyaline change of the central artery of the spleen (spleen of hypertension disease) <ul><li>The narrowing of the lumina with thickened vessel wall. Homogeneous pink hyaline material deposits under the intima. </li></ul>
    61. 97. <ul><li>Mucoid Degeneration </li></ul><ul><li>mucopolysaccharide deposition in the stroma of connective tissue. </li></ul>
    62. 98. mucoid degeneration
    63. 99. <ul><li>A heterogeneous group of pathogenic </li></ul><ul><li>fibrillar proteins accumulating in tissues </li></ul><ul><li>and organs. </li></ul><ul><li>Excess synthesis </li></ul><ul><li>Resistance to catabolism </li></ul>AMYLOIDOSIS
    64. 101. Chemical nature of amyloid fibrils Two major forms: AL (amyloid light chain protein) AA (amyloid-associated protein): Derived from serum AA (12kd) synthesized in liver and elevated in inflammatory states.
    65. 102. Minor forms of amyloid fibrils: Transthyretin (TTR): A mutant form of a serum protein in familial amyloid polyneuropathy. A variant of TTR in aging. Beta-2-microglobulin (the component of class I MHC molecules) in long-term hemidialysis.
    66. 103. Minor forms of amyloid fibrils: Beta-2-amyloid protein forms the core of cerebral plaques and deposits within cerebral vessel walls in Alzheimer disease, deriving from a transmembrane glycoprotein precursor.
    67. 104. Minor forms of amyloid fibrils: Transthyretin (TTR): A mutant form of a serum protein in familial amyloid polyneuropathy. A variant of TTR in aging. Beta-2-microglobulin (the component of class I MHC molecules) in long-term hemidialysis.
    68. 105. Minor forms of amyloid fibrils: Beta-2-amyloid protein forms the core of cerebral plaques and deposits within cerebral vessel walls in Alzheimer disease, deriving from a transmembrane glycoprotein precursor.
    69. 106. <ul><li>primary (B-cell dyscrasia, AL) </li></ul><ul><li>Secondary or reactive (AA): </li></ul><ul><li>Collagen diseases, bronchiectasis, chronic </li></ul><ul><li>osteomyelitis. </li></ul><ul><li>Hemodialysis-related: Beta-2-microglobulin </li></ul><ul><li>deposition. </li></ul><ul><li>Hereditary (AA) </li></ul>Clinical forms of amyloidosis Systemic amyloidosis:
    70. 107. <ul><li>Nodular (tumor-forming deposits, </li></ul><ul><li>B-cell dyscrasia, AL) </li></ul><ul><li>Endocrine amyloidosis (procalcitonin) </li></ul><ul><li>Amyloidosis of aging: Heart, lung, </li></ul><ul><li>pancreas, spleen, brain. </li></ul>Localized amyloidosis
    71. 109. <ul><li>Exogenous: </li></ul><ul><li>Carbon </li></ul><ul><li>Tattooing </li></ul><ul><li>Endogenous: </li></ul><ul><li>Lipofuscin </li></ul><ul><li>Melanin </li></ul><ul><li>Hemosiderin </li></ul><ul><li>Bilirubin </li></ul>Pigmentation
    72. 116. <ul><li>Dystrophic calcification </li></ul><ul><li>Metastatic calcification </li></ul>Pathologic calcification
    73. 117. <ul><li>Necrotic tissues </li></ul><ul><li>Atheroma </li></ul><ul><li>Damaged heart valves </li></ul>Dystrophic calcification
    74. 118. <ul><li>Fig 2-13 </li></ul>
    75. 120. <ul><li>Increased secretion of parathyroid </li></ul><ul><li>hormone </li></ul><ul><li>Destruction of bone tissue </li></ul><ul><li>Vitamin D-related disorders: </li></ul><ul><li>Sarcoidosis </li></ul><ul><li>Renal failure </li></ul>Metastatic calcification Hypercalcimia
    76. 121. Metastatic calcification Affecting Interstitial tissue of gastric mucosa Kidneys Lungs Pulmonary veins Systemic arteries
    77. 122. Section C CELL DEATH
    78. 123. TYPES OF CELL DEATH <ul><li>necrosis </li></ul><ul><li>Coagulation necrosis </li></ul><ul><li>Caseous necrosis </li></ul><ul><li>Gangrene </li></ul><ul><li>Liquefaction necrosis( fat necrosis) </li></ul><ul><li>Fibrinoid necrosis </li></ul><ul><li>Apoptosis </li></ul>
    79. 124. <ul><li>Swelling, denaturation and coagulation </li></ul><ul><li>of proteins </li></ul><ul><li>Breakdown of cellular organelles </li></ul><ul><li>Cell rupture </li></ul>Common type of necrosis after exogenous stimuli.
    80. 125. NECROSIS The sum of the morphologic changes that follow cell death in living tissue and organ: <ul><li>Denaturation of proteins. </li></ul><ul><li>Enzymatic digestion of organelles </li></ul><ul><li>and cytosol. </li></ul>
    81. 126. <ul><li>Enzymatic digestion by lysosomal enzymes of the dead cells themselves. </li></ul>AUTOLYSIS HETEROLYSIS <ul><li>Digestion by lysosomal enzymes of immigrant leukocytes. </li></ul>
    82. 127. <ul><li>Nucleus changes : </li></ul><ul><li>The hallmarks of cell death in three patterns: </li></ul><ul><li>Basic Pathologic Change of Necrosis </li></ul>Normal cell Chromatin margination karyorrhexis pyknosis karyolysis Nuclear Alteration of Necrosis
    83. 128. 1)Three pattern of nuclear changes Karyolysis (DNase activity) Pyknosis (DNA condensation) Karyorrhexis (fragmentation of pyknotic nucleus)
    84. 129. <ul><li>Pyknosis : nuclear shrinkage and increased basophilia, and the DNA apparently condenses into a solid, shrunken basophilic mass.  </li></ul><ul><li>Karyorrhexis: nucleus undergoes fragmentation, scattered about the cytoplasm. </li></ul><ul><li>Karyolysis: the basophilia of the chromatin may fade and the nucleus disappears. </li></ul>
    85. 131. <ul><li>Cytoplasm change: </li></ul><ul><li>increased eosinophilium and a more glassy homogeneous appearance and even vacuolated cytoplasm. </li></ul>The Necrosis of heptocytes
    86. 132. <ul><li>Types of Necrosis </li></ul>Coagulative Necrosis Liquefactive Necrosis Fibrinoid Necrosis Necrosis Gangrenous Necrosis
    87. 133. Morphologic appearance of necrosis <ul><li>Increased eosinophilia: </li></ul><ul><li>Loss of RNA in the cytoplasm </li></ul><ul><li>Increased binding of eosin to denatured </li></ul><ul><li>cytoplasmic protein </li></ul><ul><li>More glassy homogeneous appearance </li></ul><ul><li>Loss of glycogen particles </li></ul><ul><li>Vacuolated and moth-eaten cytoplasm </li></ul><ul><li>Calcification of necrotic cells </li></ul>
    88. 134. Coagulation necrosis Denatures of both structural and enzymatic proteins by injury or the subsequent increasing intracellular acidosis.
    89. 135. Renal Infarction - Coagulative
    90. 136. Splenic Infarction - Coagulative necrosis
    91. 137. Infarction - Adrenal gland:
    92. 139. Caseous necrosis A subtype of coagulation necrosis White and cheesy Tuberculosis Completely obliterated tissue architecture
    93. 140. Caseous necrosis of kidney <ul><li>The necrosis area is soft, white-yellow cheesy appearance. </li></ul>
    94. 142. Extensive Caseous necrosis Tuberculosis
    95. 144. <ul><li>Liquefactive necrosis </li></ul><ul><li>Bacterial or fungal infections </li></ul><ul><li>Central nervous system </li></ul><ul><li>Amebiasis </li></ul>
    96. 145. Liver abscess: Liquifactive necrosis
    97. 146. Stroke- Liquifactive necrosis
    98. 149. <ul><li>Fat necrosis </li></ul><ul><li>Traumatic </li></ul><ul><li>Activated pancreatic lipases </li></ul>
    99. 150. Fat necrosis(Steatonecrosis) <ul><li>Only shadowy outlines of necrotic fat cells may be seen, with basophilic calcium deposits and a surrounding inflammatory reaction. </li></ul>
    100. 151. <ul><li>Fibrinoid degeneration Deeply eosinophilic </li></ul><ul><li>Collagen diseases </li></ul><ul><li>Necrotic vasculitis </li></ul><ul><li>Malignant hypertension </li></ul>
    101. 152. Fibrinoid Necrosis <ul><li>homogeneous, deeply eosinophilic in necrosis. </li></ul>
    102. 153. <ul><li>Gangrene </li></ul><ul><li>A subtype of coagulation necrosis </li></ul><ul><li>Dry gangrene </li></ul><ul><li>Wet gangrene </li></ul><ul><li>Gas gangrene </li></ul>
    103. 154. Caseous necrosis - Tuberculosis
    104. 155. Gangrene - Amputated Diabetic foot
    105. 158. Gangrene Intestine - Thrombosis.
    106. 160. <ul><li>Absorption </li></ul><ul><li>Discharge: Erosion Ulcer </li></ul><ul><li>Sinus Fistula Cavitation </li></ul><ul><li>Organization </li></ul><ul><li>Encapsulation </li></ul><ul><li>Calcification </li></ul>Fates of necrosis
    107. 167. Section D APOPTOSIS
    108. 168. APOPTOSIS (Programmed cell death) <ul><li>Programmed destruction of cells during </li></ul><ul><li>embryogenesis. </li></ul><ul><li>Hormone dependent involution of tissues </li></ul><ul><li>in the adult. </li></ul><ul><li>Cell deletion in proliferating cell popula- </li></ul><ul><li>tions (intestinal crypt epithelium), </li></ul><ul><li>tumors, and lymphoid organs. </li></ul>
    109. 169. <ul><li>Pathologic atrophy in parenchymal </li></ul><ul><li>organs after duct obstruction. </li></ul><ul><li>Cell death by cytotoxic T cells. </li></ul><ul><li>Cell injury in certain viral diseases. </li></ul><ul><li>Cell death produced by a variety of </li></ul><ul><li>injurious stimuli given in low doses </li></ul><ul><li>(e.g. mild thermal injury). </li></ul>
    110. 170. MORPHOLOGICAL FEATURES OF APOPTOSIS <ul><li>Cell shrinkage </li></ul><ul><li>Chromatin condensation and fragmentation. </li></ul><ul><li>Formation of cytoplasmic blebs and apoptotic </li></ul><ul><li>bodies. </li></ul><ul><li>Phagocytosis of apoptotic bodies by adjacent </li></ul><ul><li>healthy cells or macrophages. </li></ul><ul><li>Lack of inflammation. </li></ul>
    111. 171. Necrosis Apoptosis Stimuli Hypoxia Physical Toxins Pathological Histology Cell swelling Single cell Coagulation N Chromatin Disruption of condensation organelles Apoptotic bodies DNA Random Internucleosomal breakdown Diffuse
    112. 172. Necrosis Apoptosis Mechanism ATP depletion Gene activation Membrane Endonuclease injury Free radicals Tissue Inflammation No inflammation reaction Phagocytosis of apoptotic bodies
    113. 173. <ul><li>Fig 1-18 </li></ul>
    114. 175. Biochemical features of apoptosis 1.PROTEIN CLEAVAGE: Caspases (cysteine protease) Nuclear scaffold Cytoskeletal protein 2.PROTEIN CROSS-LINKING: Transglutaminase Cytoplasmic protein  shrunken shalls  apoptotic bodies Biochemical features of apoptosis
    115. 176. 3. DNA breakdown: 50-300 kb pieces Ca2+, Mg2+ dependent endonucleases DNA oligonucleosomes DNA ladders (also seen in necrosis) 4. PHAGOCYTIC RECOGNITION Receptors on macrophages for the surface components (phosphatidylserine, thrombospondin) on apoptotic bodies.
    116. 177. <ul><li>Fig 1-19 </li></ul>
    117. 178. <ul><li>Apoptosis-associated genes </li></ul><ul><li>bcl-2, c-myc, p53 </li></ul>
    118. 179. <ul><li>Fig 1-20 </li></ul>
    119. 180. <ul><li>Occuring conditions </li></ul><ul><li>during embryogenesis and development; </li></ul><ul><li>as a homeostatic mechanism to maintain normal cell populations of tissue in the face of cell turnover; </li></ul><ul><li>as a defense mechanism such as in immune reactions; </li></ul><ul><li>when cells are damaged by diseases or noxious agents, such as injury, tumors and inflammation; </li></ul><ul><li>reduction cell during atrophy; </li></ul><ul><li>in aging. </li></ul>
    120. 181. <ul><li>Morphologic features </li></ul><ul><li>Cell shrinkage. </li></ul><ul><li>Chromatin condensation </li></ul><ul><li>Apoptotic bodies formation </li></ul><ul><li>Phagocytosis of apoptotic bodies by adjacent cells or macrophages. </li></ul><ul><li>Intacted membrane. </li></ul><ul><li>Morphology Biochemistry of Apoptosis </li></ul>
    121. 182. <ul><li>A specific biochemical feature </li></ul><ul><li>breakdown of DNA into large 180 to 200-kilobase pieces, by Ca 2+ /Mg 2+ dependent endogenous nucleases. </li></ul>
    122. 183. normalcell Cellular swelling, chromatin cluping Membrane damage Nuclear chromatin condensation and fragmentation Cytoplasmic budding and apoptosisi body Phagocytosisi of apoptosis body The sequential ultrastructual changes in necrosis and apoptosis
    123. 184. Apotosis of hepatocytes
    124. 185. Comparison of cell death by apoptosis and necrosis
    125. 186. Terminology: <ul><li>Necrosis: Morphologic changes seen in dead cells within living tissue. </li></ul><ul><li>Autolysis: Dissolution of dead cells by the cells own digestive enzymes. (not seen) </li></ul><ul><li>Apoptosis: Programmed cell death. Physiological, for cell regulation. </li></ul>
    126. 187. Types of Necrosis: <ul><li>Coagulative – Eg. Infarction </li></ul><ul><li>Liquifactive - Brain, abscess </li></ul><ul><li>Fibrinous - colleagen </li></ul><ul><li>Caseous - Bacterial / Tuberculosis </li></ul><ul><li>Gangrene - With infection </li></ul>
    127. 188. Ageing: <ul><li>“ Progressive time related loss of structural and functional capacity of cells leading to death” </li></ul><ul><li>Senescence, Senility, Senile changes. </li></ul><ul><li>Ageing of a person is intimately related to cellular ageing. </li></ul>
    128. 189. Factors affecting Ageing: <ul><li>Genetic – Clock genes, (fibroblasts) </li></ul><ul><li>Diet – malnutrition, obesity etc. </li></ul><ul><li>Social conditions - </li></ul><ul><li>Diseases – Atherosclerosis, diabetes etc. </li></ul><ul><li>Werner’s syndrome. </li></ul>
    129. 190. Cellular mechanisms of ageing <ul><li>Cross linking proteins & DNA. </li></ul><ul><li>Accumulation of toxic by-products. </li></ul><ul><li>Ageing genes. </li></ul><ul><li>Loss of repair mechanism. </li></ul><ul><li>Free radicle injury </li></ul><ul><li>Telomerase shortening. </li></ul>
    130. 191. Telomerase in ageing: Germ Cells Somatic Cells
    131. 192. Ageing –changes: <ul><li>Gradual atrophy of tissues and organs. </li></ul><ul><li>Dementia </li></ul><ul><li>Loss of skin elasticity </li></ul><ul><li>Greying and Loss of hair </li></ul><ul><li>BV damage – atherosclerosis/bruising. </li></ul><ul><li>Loss of Lens elasticity  opacity  vision </li></ul><ul><li>Lipofuscin pigment deposition – Brown atrophy in vital organs. </li></ul>
    132. 193. Pathology of elderly
    133. 194. Factors affecting ageing: <ul><li>Stress </li></ul><ul><li>Infections </li></ul><ul><li>Diseases </li></ul><ul><li>Malnutrition </li></ul><ul><li>Accidents </li></ul><ul><li>Diminished stress response. </li></ul><ul><li>Diminished immune response. </li></ul><ul><li>Good health. </li></ul>
    134. 195. Conclusions: <ul><li>Cellular Injury - Various causes </li></ul><ul><li>Reversible Injury  Adaptations </li></ul><ul><ul><li>Hypertrophy, Hyperplasia, Atrophy </li></ul></ul><ul><ul><li>Accumulations - Hydropic, hyaline, fat.. </li></ul></ul><ul><li>Irreversible Injury - Necrosis </li></ul><ul><ul><li>Coagulative, Liquifactive, Caseous </li></ul></ul><ul><li>Ageing - Causes, Changes, Factors </li></ul>

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