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02&03&04_Adaptation ,Cell Injury & Death.pdf
- 1. IN THE NAMEOF GOD
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- 3. Definitions Pathology = bridgingbetween clinical & basic science there is four stages for any disease 1.Etiology (cause) 2.Pathogenesis (Mechanism of development of disease) 3.Morphology (changes in the gross and microscopic) 4.Diagnosis
- 5. • Normal homeostasis: The cell tend to preserve its intracellular milieu within a narrow range of physiologic parameter . • By physiologic stress ,or pathologic stimulus the cell undergo adaptation with a new steady state preserving viability.
- 6. If theadaptive capacity is exceeded cell develop injury Cell injury up to a point is reversible . With severe or persistent stress irreversible injury.
- 8. Adapted myocyte (hypertrophy) Normalmyocyte Reversible injury (Ischemia) Cell death (infarction)
- 11. Different changes ofmyocardial cell after ischemia Cellular function ---------- Cell death ----------------- Ultrastructural changes--- Light microscopic--------- changes Gross morphologic-------- changes (Pallor) After 1-2 min After 20-30 min After 2-3 hours After 6-12 hours After 24-72 hours
- 12. Cellular adaptation 1)Atrophy shrinkage insize of the cell (so the organ ↓ in size) atrophic cell ↓ function but not dead . Causes: ↓ workload , ↓ nutrition, loss of innervation , ↓ endocrine stimulation , menopause, ↓ blood supply , aging
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- 16. Cellular adaptation 2) Hypertrophy ↑in size of the cell (so ↑ in size of the organ) Physiologic: uterus during pregnancy ( estrogen stimulation) skeletal muscle in weight lifter Pathologic: cardiac enlargement in chronic hypertension
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- 20. Cellular adaptation 3)Hyperplasia ↑ innumber of cells (so ↑ in size of the organ) Physiologic: breast at puberty (Hormonal) when a portion of liver is removed (compensatory) Endometrial hyperplasia ( estrogen stimulation) Pathologic: prostatic hyperplasia hyperplasia of fibroblast and blood vessels in repair wart (HPV) (cancer ) & hyperplasia
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- 22. 4) Metapalsia : Adultcell type is replaced by another adult cell type Cellular adaptation
- 23. Respiratory epithelium: pseudostratified ciliatedcolumna squameous cigarette , vit A deficiency Esophageal epithelium: squameous Gastric or intestinal mucosa (in reflux) Barrett’s metaplasia Soft tissue: fibroblast osteoblast or chondroblast in scapula osseous metaplasia Cervix , endocervix: columnar squamous Squamous metaplasia
- 26. METAPLASIA 1- Squamous metaplasia Cervix: Columnarinto squamous 2- Barrett metaplasia Esophagus: Squamous into columnar
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- 28. Cell Injury and CellDeath Reversible cell injury :In mild forms of injury the functional and morphologic changes are reversible Structural and functional abnormalities No progression to severe membrane damage and nuclear dissolution. Cell death: With continuing damage the injury becomes irreversible and cell death occurs Two types of cell death : Necrosis and apoptosis
- 30. Necrosis Damage tomembranes Enzymes leak out of lysosomes Digest the cell, resulting in necrosis Leak of cellular contents through the damaged plasma membrane and host reaction (inflammation) Necrosis is the major pathway of cell death in ischemia, toxins, various infections, and trauma
- 31. Fig. 2.3 Reversiblecell injury and necrosis . The principal cellular alterations that characterize reversible cell injury and necrosis are illustrated . By convention, reversible injury is considered to culminate in necrosis if the injurious stimulus is not removed.
- 32. Apoptosis Cell deprivationof growth factors Damage to cell's DNA or proteins beyond repair Nuclear dissolution without complete loss of membrane integrity Active, energy dependent, tightly regulated type of cell death in specific situations Necrosis is always a pathologic process Apoptosis play many normal functions and is not always associated with pathologic cell injury
- 34. Causes of cellinjury 1)Hypoxia (oxygen deficiency) defect in aerobic oxidative respiration important and common cause of cell injuy a. ischemia : most common cause of hypoxia loss of blood supply b. Inadequate oxygenation of blood cardiorespiratiry failure , pneumonia c. Loss of oxygen carrying capacity of the blood anemia or carbon monoxide poisoning
- 36. Causes of cellinjury . . . 2) Physical agents trauma , changes in temperature , radiation electrical injury , changes in atmospheric pressure
- 37. Causes of cellinjury . . . 3)Chemicals and drugs any chemical agent may cause injury glucose or salt , if concentrated cause injury (affect the osmolarity of environment)
- 38. Causes of cellinjury . . . Air pollutant Insectisides Carbon monoxide Asbestose Ethanol
- 39. Causes of cellinjury . . . 4)Microbiologic agents Virus Rickettsiae Bacteria Fungus parasite
- 40. Causes of cellinjury . . . 5) Immunologic reaction • anaphylactic reaction to a foreign protein • immunologic reaction to self-antigen
- 41. Causes of cellinjury . . . 6)Genetic defects amino acid substitution in sickle cell anemia , trisomy 21 in down syndrome
- 42. Causes of cellinjury . . . 7)Nutritional imbalance protein-calorie insufficiency specific vitamins diet rich in animal fat : atherosclerosis brain , heart
- 43. Causes of cellinjury . . . 8)Aging alterations in replicative capacity and repair abilities diminished ability to respond to damage
- 44. Morphology of CellInjury Molecular and biochemical changes Loss of cellular function Two phenomena characterize irreversibility: 1-The inability to correct mitochondrial dysfunction (lack of ATP generation) 2-Profound disturbances in membrane function
- 45. Fig. 2.5The relationship among cellular function, cell death, and the morphologic changes of cell injury. Note that cells may rapidly become nonfunctional after the onset of injury, although they are still viable, with potentially reversible damage; with a longer duration of injury, irreversible injury and cell death may result. Note also that cell death typically precedes ultrastructural, light microscopic, and grossly visible morphologic changes.
- 46. Morphology of ReversibleInjury Cellular swelling : failure of energy dependent ion pumps in the plasma membrane Fatty change : in hypoxic , toxic and metabolic injury small and large vacuoles in cytoplasm
- 47. Cellular Swelling Pallorat gross examination Increased turgor. Increase in weight of the organ Small, clear vacuoles within the cytoplasm Distended and pinched-off segments of the endoplasmic reticulum (ER) Hydropic change or vacuolar degeneration
- 48. Fatty change Lipidvacuoles in the cytoplasm Cells participating in fat metabolism Hepatocytes and myocardial cells Injured cells may show increased eosinophilic staining
- 49. Intracellular Changes AssociatedWith Reversible Injury Plasma membrane :blebbing, blunting, or distortion of microvilli, and loosening of intercellular attachments Mitochondrial changes :swelling and phospholipid-rich amorphous densities Dilation of the ER with detachment of ribosomes and dissociation of polysomes Nuclear alterations, with clumping of chromatin Phospholipid masses. called myelin figures
- 50. Fig. 2.3 Reversiblecell injury and necrosis.The principal cellular alterations that characterize reversible cell injury and necrosis are illustrated.By convention, reversible injury is considered to culminate in necrosis if the injurious stimulus is not removed.
- 51. Fig. 2.4Morphologic changes in reversible and irreversible cell injury (necrosis). (A) Normal kidney tubules with viable epithelial cells. (B) Early (reversible) ischemic injury showing surface blebs, increased eosinophilia of cytoplasm, and swelling of occasional cells. (C) Necrotic (irreversible) injury of epithelial cells, with loss of nuclei and fragmentation of cells and leakage of contents.
- 52. Morphology of Necrosis Cytoplasmic changes: -Increased eosinophilia -Loss of the basophilia -More glassy, homogeneous appearance -Loss of glycogen particles -Myelin figures are more prominent -Vacuolated cytoplasmic "moth-eaten"
- 53. Morphology of Necrosis. . . Cytoplasmic changes: -Electron microscopy shows discontinuities in plasma and organelle membranes -Marked dilation of mitochondria with the appearance of large amorphous densities -Disruption of lysosomes , intracytoplasmic myelin figures
- 54. Morphology of Necrosis. . . Nuclear changes : -(pyknosis) nuclear shrinkage and increased basophilia DNA condenses into a solid shrunken mass. -(karyorrhexis) the pyknotic nucleus undergoes fragmentation - (karyolysis) the basophilia fades because of digestion of DNA by deoxyribonuclease (DNase) activity. In 1 to 2 days, the nucleus in a dead cell may completely disappear.
- 55. Morphology of Necrosis. . . Necrotic cells may persist for some time or digested by enzymes Dead cells may be replaced by myelin figures, which are either phagocytosed or degraded into fatty acids Fatty acids bind calcium salts so dead cells becoming calcified
- 56. Other Pathways ofCell Death Necroptosis initiated by engagement of TNF receptors as well as other, poorly defined triggers receptor-interacting protein (RIP) kinases are activated, initiating a series of events that result in the dissolution of the cell, much like necrosis features of both necrosis and apoptosis Some infections , ischemic injury , pathologic situations, associated with inflammatory reactions in which the cytokine TNF is produced
- 57. Pyroptosis activationof a cytosolic danger-sensing protein complex called the inflammasome The net result of inflammasome activation is the activation of caspases, some of which induce the production of cytokines that induce inflammation, often manifested by fever, and others trigger apoptosis apoptosis and inflammation coexist The name pyroptosis stems from the association of apoptosis with fever (Greek, pyro = fire) some infectious microbes
- 58. Autophagy Autophagy (“self-eating”): lysosomal digestion of the cell’s own components. survival mechanism in times of nutrient deprivation, so that the starved cell can live by eating its own contents and recycling these contents to provide nutrients and energy. Extensive autophagy is seen in ischemic injury and some types of myopathies. If the stress is too severe for the process to cope with it, it results in cell death by apoptosis.
- 59. Fig. 2.14Autophagy. Cellular stresses, such as nutrient deprivation, activate autophagy genes, which initiate the formation of membrane- bound vesicles in which cellular organelles are sequestered. These vesicles fuse with lysosomes, in which the organelles are digested, and the products are used to provide nutrients for the cell. The same process can trigger apoptosis by mechanisms that are not well defined.
- 60. Mechanisms of cellinjury and cell death Before discussing individual mechanisms of cell injury and death, some general principles should be emphasized. The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity. The consequences of an injurious stimulus also depend on the type, status, adaptability, and genetic makeup of the injured cell Cell injury usually results from functional and bio chemical abnormalities in one or more of a limited number of essential cellular components
- 61. Mechanisms of cellinjury and cell death: Hypoxia and Ischemia Oxidative Stress Ischemia-Reperfusion Injury Cell Injury Caused by Toxins Endoplasmic Reticulum Stress DNA Damage Inflammation
- 62. Fig. 2.15 Theprincipal biochemical mechanisms and sites of damage in cell injury. Note that causes and mechanisms of cell death by necrosis and apoptosis are shown as being independent but there may be overlap; for instance, both may contribute to cell death caused by ischemia, oxidative stress, or radiation. ATP, Adenosine triphosphate; ROS, reactive oxygen species.
- 65. The consequences ofan injury are dependent on: the type of cell being injured myocardial muscle 20-30 min skeletal muscle 2-3 hours brain 3-5 min
- 66. Four intracellular systemsare particularly vulnerable 1) cell membrane integrity critical to cellular ionic and osmotic homeostasis 2) aerobic respiration , ATP 3) protein synthesis , structural and enzymatic 4) The integrity of genetic apparatus
- 67. Ischemic and hypoxicinjury: Reversible injury: First effect of hypoxia is on: (oxidative phosphoryation by mitochondria) intracellular generation of ATP is decreased Na pump Ischemia ATP Glycolysis protein synthesis
- 68. 1) ATP Napump influx of Ca ++ , H2o, Na+ efflux of k cellular swelling , cellular bleb loss of microvilli , E.R. Swelling 2) ATP AMP phosphofructokinase anaerobic glycolysis glycogen is rapidly depleted lactic acid PH (clumping of nuclear chromatin) PH inorganic phosphate 3) ATP detachment of ribosome from RER dissociation of polysome into monosome protein synthesis lipid deposition Fatty change
- 69. Ischemia-Reperfusion Injury Restorationof blood flow to ischemic but viable tissues results, paradoxically, in exacerbated and accelerated injury 1) Increased generation of ROS from parenchymal and endothelial cells and from infiltrating leukocytes
- 70. Ischemia-Reperfusion Injury 2) Actionof oxidases in leukocytes, endothelial cells, or parenchymal cells 3) Increased inflammation after reperfusion 4)Activation of the complement system 5)Some antibodies have a propensity to deposit in ischemic tissues After reperfusion complement binds and exacerbate injury and inflammation
- 71. Oxidative stress Oxidativestress refers to cellular abnormalities that are induced by ROS, which belong to a group of molecules known as free radicals
- 72. Free radicals: Are chemicalspecies with: a single unpaired electron in an outer orbital Free radical is unstable Readily react with inorganic or organic chemicals. Free radicals initiate autocatalytic reaction (molecules that react with free radicals are in turn converted into free radicals , CHO , prot , lipid…)
- 73. Generation of freeradical within the cell: ROS are produced normally in small amounts in all cells during the reduction-oxidation (redox) reactions that occur during mitochondrial respiration and energy generation ROS are produced in phagocytic leukocytes, mainly neutrophils and macrophages, as a weapon for destroying ingested microbes and other substances during inflammation and host defense Nitric oxide (NO) is another reactive free radical produced in macrophages and other leukocytes.
- 74. The generation offree radicals is increased under several circumstances: The absorption of radiant energy (e.g., ultraviolet (UV) light, x-rays). The enzymatic metabolism of exogenous chemicals (e.g., carbon tetrachloride) Inflammation, in which free radicals are produced by leukocytes Reperfusion of ischemic tissues
- 75. some free radicalsdecay spontaneusly 2O• 2+2H H2O2+O2 Glutathione (GSH) peroxidases : 2GSH + H2O2 → GS-SG + 2H2O Catalase : (2H2O2 → O2 + 2H2O) antioxidants (vit E,vit A,vit C, ß-carotene) block free radical formation or destruction of free radicals superoxide dismutase Found in many cells How free radicals are eliminated from the cell:
- 77. ROS causes cellinjury by damaging multiple components of cells Lipid peroxidation of membranes Crosslinking and other changes in proteins. DNA damage.
- 80. Cell Injury Causedby Toxins Direct-acting toxins mercuric chloride poisoning anti-neoplastic chemotherapeutic agents toxins made by microorganisms Latent toxins. Carbon tetrachloride (CCl4) acetaminophen
- 81. toxic chemicals notinitially active but must be converted to active form. this conversion occur in the: << P-450 oxidase system>> in the SER of hepatocyte memb phospholipid peroxidation eg: CCL4 CCL3 breakdown of E.R Results:in 30 min : hepatocyte protein synth in 2 hours: swelling of SER, dissociation of ribosome later: Reduced lipid export from hepatocyte ( Apoprot synthesis to complex with TG) fatty change , mitoch. Injury ,cellular injury lipid peroxidation ( by fatty aldehyde) ca inside the cell P-450 Oxidase system Enz structural Cell Injury Caused by Toxins
- 82. Endoplasmic Reticulum Stress The accumulation of misfolded proteins in a cell can stress compensatory pathways in the ER and lead to cell death by apoptosis. Intracellular accumulation of misfolded proteins may be caused by abnormalities that increase the production of misfolded proteins or reduce the ability to eliminate them Gene mutations Aging Infections :viral infections Neurodegenerative diseases Deprivation of glucose and oxygen, as in ischemia and hypoxia
- 83. Protein misfoldingwithin cells may cause disease by creating a deficiency of an essential protein or by inducing apoptosis. Endoplasmic Reticulum Stress
- 84. Misfolded proteinsoften lose their activity and are rapidly degraded, both of which can contribute to a loss of function. cystic fibrosis Cell death as a result of protein misfolding Alzheimer disease, Huntington disease, and Parkinson disease, and may underlie type 2 diabetes
- 87. DNA Damage Exposureof cells to radiation or chemotherapeutic agents, intracellular generation of ROS, and acquisition of mutations may all induce DNA damage, which if severe may trigger apoptotic death. p53 protein
- 88. Inflammation pathogens, necroticcells, and dysregulated immune responses, as in autoimmune diseases and allergies In all these situations, inflammatory cells, including neutrophils, macrophages, lymphocytes, and other leukocytes, secrete products that evolved to destroy microbes but also may damage host tissues. hypersensitivity
- 89. Common Events inCell Injury From Diverse Causes Mitochondrial Dysfunction • Failure of oxidative phosphorylation • Abnormal oxidative phosphorylation • formation of a high-conductance channel in the mitochondrial membrane, called the mitochondrial permeability transition pore • cytochrome c Defects in Membrane Permeability • Mitochondrial membrane damage • Plasma membrane damage. • Injury to lysosomal membranes
- 90. Fig. 2.19 Roleof mitochondria in cell injury and death. Mitochondria are affected by a variety of injurious stimuli and their abnormalities lead to necrosis or apoptosis.
- 91. Necrosis: Morphologic changes thatfollow cell death in living tissue Necrosis results from two processes: *Enzymatic digestion of the cell *Denaturation of proteins dead cell =autolysis invading inflammatory cells=heterolysis
- 92. Major types ofnecrosis Coagulative necrosis Liquefactive necrosis Gangrenous necrosis Caseous necrosis Fat necrosis Fibrinoid necrosis
- 93. Types of necrosis Coagulativenecrosis: Morphology , preservation o f outlines of the cells (for several days ) Enzymatic prot Acidosis cause denaturation of Structural prot eg: myocardial infarction : acidophilic anucleate cells (for weeks) hypoxic ingury in all tissues (except brain ) Liquifactive necrosis: Focal bacterial (or sometimes fungal )infection accumulation of WBC heterolysis of dead cells Cell death in CNS is liquifactive neccrosis liquifaction completely digest the dead cell
- 94. Coagulative necrosis ,kidney Loss of nuclei Clumping of the cytoplasm Preservation of basic outline of tubules and glomeruli
- 96. Fig. 2.6coagulative necrosis. (A) A wedge-shaped kidney infarct (yellow) with preservation of the outlines. (B) microscopic view of the edge of the infarct, with normal kidney (N) and necrotic cells in the infarct (I).The necrotic cells show preserved outlines with loss of nuclei, and an inflammatory infiltrate is present (difficult to discern at this magnification)
- 97. Splenic Infarction -Coagulative necrosis
- 98. Liquifactive necrosis • Bacterialor fungal infection • Abscess containing white cells and cellular debris • Normal architecture of the tissue is not seen. • Brain infarction
- 99. Liquefactive necrosis Hydrolasescause tissue to become soft, often cyst form Occurs in brain Causes: bacterial infection such as staphylococci, streptococci and E. coli
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- 101. Liver abscess: Liquifactivenecrosis
- 102. Gangrenous necrosis : Ischemiccoagulative necrosis of a limb When superimposed bacterial infection: Wet gangrene Severe hypoxia Occurs in lower leg precipitated by arteriosclerosis, and in diabetes Foul smell, black color is caused by the gangrene organisms
- 104. Gangrene - AmputatedDiabetic foot
- 105. Dry gangrene Iscoagulative necrosis Skin black and wrinkled due to interrupted arterial supply result is coagulative necrosis tissue dies and dries up, turns black occurs in superficial tissues of periphery
- 106. Dry gangrene ina person with peripheral vascular disease secondary to diabetes mellitus
- 107. Wet Gangrene interruptedvenous return is common cause bacteria accumulate liquefactive necrosis usually in internal organs but also occurs in extremities Neutrophils invade and cause liquefactive necrosis Occurs internally
- 109. Gangrene - AmputatedDiabetic foot
- 110. Caseous necrosis : (Granulomatousreaction) A type of necrosis in tuberculosis Epitheloid histiocyte , giant cell :Granuloma Composed of structurless amorphous granular debris and fragmented coagulated cell in the center.
- 111. Caseous necrosis Hydrolasesdo not completely digest tissue, pockets form looks like clumped cheese (caseous) (white, cheesy ) Occurs in lung ,(tuberculosis) Cause- often infection with Mycobacterium tuberculosis
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- 115. Caseous necrosis -Tuberculosis
- 116. Fat necrosis: Focal areaof fat destruction Typically seen in pancreatic injury Pathologic release of pancreatic enzymes Liquifying fat cell membrane hydrolyzing the TG esters in the memb Released fatty acids + Ca++ fat saponification morphology : shadowy outline of necrotic fat cell basophilic Ca++ deposits
- 117. Fat necrosis Lipasesbreak down triglycerides and release free fatty acids which form soaps when they combine with cations such as Ca++, Na+ Occurs in breast and pancreas, other abdominal organs, Mesenteric fat
- 119. Fibrinoid Necrosis Inimmune reactions involving blood vessels Ag-Ab complex deposition in wall of arteries Bright pink and amorphous appearance in H&E stain called fibrinoid
- 121. Subcellular Responses toInjury 1) Autophagy :lysosomal digestion of cell components 2) Heterophagy : cell (macrophage) ingests substances from the outside for intracellular destruction Lysosomes with undigested debris may persist as residual bodies 3) Lipofuscin pigment : indigestible material from free radical- mediated lipid peroxidation
- 122. Subcellular Responses toInjury 4) Induction (Hypertrophy) of Smooth ER: smooth ER is involved in the metabolism of various chemicals 5) Mitochondrial alterations : in the number,size, shape, and function of mitochondria Large and abnormal shapes (megamitochondria),in hepatocytes in nutritional deficiencies and alcoholic liver disease
- 123. Subcellular Responses toInjury 6) Cytoskeletal Abnormalities: Intracellular transport of organelles and molecules Maintenance of basic cell architecture transmission of cell-cell and cell-extracellular matrix signals to the nucleus Maintenance of mechanical strength for tissue integrity Cell mobility Phagocytosis
- 124. Apoptosis A pathwayof cell death Activation of enzymes for degrading DNA and proteins Plasma membrane is intact but altered for targeting of phagocytosis Dead cell is rapidly cleared before leaking of their enzymes Differ from necrosis (host reaction)
- 125. Causes Of Apoptosis For eliminating harmfull cells and out lived cells When cell damage is severe that affects DNA and protein
- 127. Apoptosis: Physiologic Conditions: Programmeddestruction of cells during embryogenesis Involution of hormone dependent tissues upon hormonal deprivation (endometrial ) Cell loss in proliferating cell population (maintenance of constant number) Death of cells at the end of their function (PMN and lymphocytes)
- 128. Apoptosis : Physiologic Conditions Elimination of harmfull cell reactive lymphocytes Cell death induced by cytotoxic T lymphocytes
- 129. Apoptosis : Pathologic Conditions Elimination of genetically altered and injured cells with no repair No host reaction 1)DNA damage : radiation , chemotherapy, extreme of temperature , hypoxia 2)Inducing apoptosis in cancer cells 3)Accumulation of misfolded proteins
- 130. Apoptosis : Pathologic Conditions 4)Insome infections induced by viruses (adenovirus and HIV) or host immune response (viral hepatitis) 5)Pathologic atrophy in parenchymal organs after duct obstruction (pancreas-parotid- kidney)
- 131. Morphology Of Apoptosis Cellular masses with intensly eosinophilic cytoplasm Nuclei; chromatin condensation and then karyorrhexis Fragmentation of DNA Shrinkage of cells-cytoplasmic buds-fragments of apoptotic bodies Quick phagocytosis with no inflammation
- 132. Fig. 2.11 apoptosis.The cellular alterations in apoptosis are illustrated. Contrast these with the changes that characterize necrotic cell death,shown in fig. 2.3.
- 134. Mechanism Of Apoptosis Activation of caspase system (cysteine proteases that cleave proteins after aspartic residues) Activation of nuclease ,protease and other enzymes for degrading nucleoprotein and structural protein
- 136. Pathways of apoptosis Contains proteins for inducing apoptosis like cytochrome C and antagonists of apoptosis inhibitors Permeability of mitochondria is controlled by BCL-2 protein family DNA damage causes activation of proapototic members (Bax – BaK) 1)Mitochondrial(Intrinsic) Pathway
- 137. Mitochondrial(Intrinsic) Pathway (Bax– BaK) dimerize and insert into the mitochondrial membrane, and form channels through which cytochrome c and other mitochondrial proteins escape into the cytosol Cytochrome activate caspase system leading to nuclear fragmentation.
- 138. Mitochondrial(Intrinsic) Pathway Ifcells are exposed to growth factors and other survival signals, they synthesize antiapoptotic members of the Bcl-2 family (Bcl-2 itself and Bcl-xL )
- 139. 2)Death Receptor(Extrinsic) Pathway Many cells express death receptor at surface that trigger apoptosis (TNF receptor & FAS) Activated T cells express FAS ligand FAS ligand + FAS causes activation of caspase system The death receptor pathway is involved in the elimination of self- reactive lymphocytes and in the killing of target cells by some cytotoxic T lymphocytes (CTLs) that express FasL.
- 140. Clearance Of ApoptoticCells Phosphatidylserin express to outer leaflet of plasma membrane recognized by phagocytes Release of soluble factors recruits phagocytes
- 142. Intracellular accumulation Normal cellmay accumulate : abnormal amount of substances harmless transient cytoplas synthetized by cell Injury permanent nucleus by other cell
- 143. Fatty change (steatosis): Abnormalaccumulation of Triglycerides within parenchymal cells mostly reversible, sometimes Irreversible Fatty change is seen in : Liver , heart , skletal muscle, kidney Fatty change may be caused by: Toxins Obesity Protein malnutrition Anoxia Diabetes mellitus Alcohol
- 146. Cholestrol In smooth musclecell Machrophage Yellow plaque Hereditary aquired Machrophages in the skin or tendon = xanthoma Hyperlipidemic synd Cholestrol or cholestrol esters Atherosclerosis
- 147. Proteins Kidney:Alb inprox con tubule reabsorbed by pinocytosis fusion of Alb-lysosome : pink hyalin cytoplasmic droplet it is reversible Plasma cell: Ig in RER, round eosinophilic Russell body Alcoholic hyaline (Mallory body)
- 148. Glycogen Diabetes mellilus:defect in glucose metabolism Glycogen accumulate Kidney: renal tubular epith heart: myocyte Liver: hepatocyte Pancrease:-cell
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- 150. 1-Exogenous: carbon smallamount of carbon alveolar mach - lymphnode = anthracosis heavy exposure fibroblastic reaction = coal worker pneumoconiosis
- 151. 2-Endogenous: Lipofuscin: wear andtear pigment insoluble brownish yellow pigment (brown atrophy) accumulate with age or in atrophic organs Organs: heart liver brain It is complexes of lipid and protein derived from peroxidation of polyunsaturated lipids of organellar membrane.(by free radicals) It is a marker of past free radical injury
- 153. Melanin: brown black pigment tyrosinDHPA produced in melanocytes (protect agaist U.V.) adjacent basal keratinocytes in the skin can accumulate melanin (eg:in freckles) or in pigmanted nevus melanin accumulate oxidation
- 154. Hemosiderin golden yellow pigmentwith excess iron iron store with apoferritin (ferritin micelle ) inside the cell Hemosiderin=Large aggregate of ferritin micelle Staining for iron=Prussian blue normally small amount of iron in Systemic overload of iron= =Hemosiderin deposition in many organs = Hemosiderosis Bone marrow Spleen liver
- 155. Hemosiderin accumulationis usually pathologic. Small amounts of this pigment are normal in the mononuclear phagocytes of the bone marrow, spleen, and liver, where aging red cells are normally degraded. Excessive deposition of hemosiderin, called hemosiderosis, and more extensive accumulations of iron seen in hereditary hemochromatosis.
- 156. Hemosiderin granules inliver cells A- Golden-brown granular pigment (H&E) in the cytoplasm of hepatocytes B- oxidized Fe +++ of hemosiderin Stained blue by prussian blue reaction
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- 161. Pathologic calcification 1.Dystrophic calcification: deposition of Ca++ in the necrotic tissue serum level of Ca++ is normal atherosclerosis of aorta of heart vulve deposition Gross : fine white granule lymph node involved by T.B. Stone intracellular extracellular Finally Ca++ + phosphate calcium phosphate (crystal formation) eg: cause organ dysfunction Histo : calcification basophilic deposits
- 162. Dystrophic calcification Aorticvalve in old age damaged valve Cause calcific aortic stenosis Will prevent normal opening of the valve • may be an incidental finding indicating insignificant past cell injury
- 164. Metastatic calcification: deposition ofCa++ in normal tissue serum level of Ca ++is hypercalcemia location : interestitial tissue of : vesseles , kidney ,lung , gastric mucosa Calcium salt formation :similar to dystrophic calcification. (Nephrocalcinosis)
- 167. occur widelythroughout the body but principally affects the interstitial tissues of the vasculature, kidneys, lungs, and gastric mucosa. They generally do not cause clinical dysfunction, extensive calcifications in the lungs may be evident on radiographs and may produce respiratory deficits, massive deposits in the kidney (nephrocalcinosis) can lead to renal damage.
- 168. The major causesof hypercalcemia are 1) Increased secretion of parathyroid hormone: primary parathyroid tumors , production of parathyroid hormone– related protein by other malignant tumors; 2) Destruction of bone due to the effects of accelerated turnover (e.g., Paget disease), immobilization, or tumors (increased bone catabolism associated with multiple myeloma, leukemia, or diffuse skeletal metastases); 3) vitamin D–related disorders : vitamin D intoxication , sarcoidosis (in which macrophages activate a vitamin D precursor) 4) renal failure: phosphate retention leads to secondary hyperparathyroidism.