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Ischemic/hypoxic injuryOxygen Oxydative phosphorilation ATP production Sodium pump GlycogenolysisRibosome detachmentInjury due to Free RadicalsFree Radicals: atoms or molecules possesing unpaired electron in an outer orbitCharacteristics of free radicals:react with any organic / inorganic substancethe results will form a new free radicals new reaction chainthe reaction will cease by itself or by enzymatic reaction

Plasma MembraneNucleus

Golgi Apparatus

MitochondriaLisosome & peroxisome

The smooth endoplasmic reticulum

The rough endoplasmic reticulum

Cytoskeleton

Microtubules

Actin filaments

Intermediate filamentsCellular adaptation to stress

Cellular Adaptations of Growth and DifferentiationHyperplasiaHypertrophyAtrophyMetaplasiaHyperplasiaAn increase in the number of cells in an organ or tissuePhysiologic:CompensatoryHormonalPathologicPathologic hyperplasia constitutes a fertile soil in which cancerous proliferation may eventually arise.Hypertrophyan increase in the size of cells, resulting in an increase in the size of the organ.

Atrophya decrease in the size of an organ that has reached its normal size Decreased workload (disuse atrophy)Loss of innervation (denervation atrophy)Diminished blood supplyInadequate nutritionLoss hormonal stimulationSenile atrophyPressure atrophy

Metaplasiaa reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type

Cell injury and cell deathCauses of cell injuryHypoxiaFree radicalsPhysical injuryChemical injuryInfectionImmune reaction

InflammationHypoxiaChemicalReperfusionRadiationAgingIschemia

Ischemic/hypoxic injuryOxygen Oxydative phosphorilation ATP production Sodium pump GlycogenolysisRibosome detachmentSodium pump Influx Ca ++ Na+ Retension Efflux K+ Cell swollen Microvilli disappear Bleb formation ER swollen Myelin bodiesIschemic/hypoxic injuryOxygen Oxydative phosphorilation ATP production Sodium pump GlycogenolysisRibosome detachmentGlycogenolysis Lactic acid and inorganic phosphate pH Chromatin clumpsIschemic/hypoxic injuryOxygen Oxydative phosphorilation ATP production Sodium pump GlycogenolysisRibosome detachmentDetachment of ribosomesProtein production Intracellular osmotic pressure Cell edema

IskemiaInflammationHypoxiaChemicalReperfusionRadiationAgingThree important free radicals:Superoxide anion radical (O2)Hydrogen peroxide (H2O2)Hydroxyl ions(OH)Effects of free radicals on cell membrane:Membrane lipid peroxidation (especially by OH)Protein damage: cross-linking of amino acids, increase protease activationDNA damage: single helix formation followed by cell death of even malignant transformation (cancer)De-activation of free radicalsSpontaneous, because of its instabilityEndogenous/exogenous antioxidantVitamine E, C and ABinding to storage & transport proteins (lactoferrin, ceruloplasmine, dan trasferrin)EnzymaticSuperoxide dismutase (SOD)CatalaseGlutathione peroxidase

S.O.D,Catalase,and Gluthation peroxidase are free radical-scavenging enzymesChemical injury (cont)Lipid solubleIndirect effects (converted to reactive toxic metabolites, which then act on target cells)E.g: CCl4

Myelin figuresER swellingRibosomes detachmentMitochondrial swellingSmall densitiesBlebsCell swellingChromatin clumpsAutophagy

ABCReversibleIrreversibleNormal

ATP Phospholipid synthesis Ca++ Phospolipase activationPhospholipid degradationCytoskeletal damageMembrane damageMechanisms membrane damage(made simple)Protease activationMembrane defectsMyelin figuresLysis of ERMitochondrial swellingLarge densitiesNucleus pyknosis

Rupture of lysosomesCell DeathCould be necrosis or apoptosisNecrosisCell death in association to a living tissue When due to lisosomal enzymes: autolysis, due to enzymes of immigrant cells: heterolysis.Autolysis coagulative necrosis; heterolysis liquefactive necrosis Morphological changes occure within hoursThe morphology of necrotic cellsCytoplasm:Eosinophillic (reaction to denatured proteins) Glassy appearance (due to loss of glykogen particles)Vacuolated (due to digestion of organelles)CalcificationNucleus: (3 possibilities)Pyknosis (due to nuclear shrinkage)Karyorhexis (fragmentation of the pyknotic nucleus)Karyolisis (basophilia of the chromatine fades)

NormalNecrosisThe cytoplasm is more eosinophillicNuclei partially lysis

H & E staining to show edema of the myocardial fibresLDH enzyme stainingto area unstained areasMorphology of necrosisCoagulative necrosis: The cell outlines are maintained Characteristic to hypoxic necrosis exept on the brain.

Occur because the lysosomal enzymes we also damaged

Liquefactive necrosis: Due to autolysis or heterolysis Characteristic to bacterial infection (pus) and hypoxic necrosis to the brain

Gangrenous necrosis: infected coagulative necrosis (may then turns to liquefactive necrosis)

Caseous necrosis Special form of coagulative necrosis, spesific to tbc Macroscopically looks like cheese

Microscopic: amorphous mass, granular, surrounded by inflammatory cellsEnzymic fat necrosis

Destruction of fat due to pancreatic lipase Fatty acid formed will bind to calcium Microscopic: necrotic area, calcium deposition (blue), and inflammation of the surrounding tissue

Fibrinoid necrosisApoptosisCould be physiological or pathologicalProgrammed cell death in embryogenesis, involusion of hormon dependent organs, cell death in cancer, etc)Morphology:ShrinkageChromatin condensationFormation of blebs and apoptotic bodiesPhagocytosis of apoptotic bodies

APOPTOSISNECROSIS

Mechanisms of apoptosis. The two pathways of apoptosis differ in their induction and regulation, and both culminate in the activation of "executioner" caspases. The induction of apoptosis by the mitochondrial pathway involves the action of sensors and effectors of the Bcl-2 family, which induce leakage of mitochondrial proteins. Also shown are some of the anti-apoptotic proteins ("regulators") that inhibit mitochondrial leakiness and cytochrome c-dependent caspase activation in the mitochondrial pathway. In the death receptor pathway engagement of death receptors leads directly to caspase activation. The regulators of death receptor-mediated caspase activation are not shown.58

The intrinsic (mitochondrial) pathway of apoptosis. A, Cell viability is maintained by the induction of anti-apoptotic proteins such as Bcl-2 by survival signals. These proteins maintain the integrity of mitochondrial membranes and prevent leakage of mitochondrial proteins. B, Loss of survival signals, DNA damage, and other insults activate sensors that antagonize the anti-apoptotic proteins and activate the pro-apoptotic proteins Bax and Bak, which form channels in the mitochondrial membrane. The subsequent leakage of cytochrome c (and other proteins) leads to caspase activation and apoptosis.59

Apoptotic bodies

Mechanisms of protein folding and the unfolded protein response. A, Chaperones, such as heat shock proteins (Hsp), protect unfolded or partially folded proteins from degradation and guide proteins into organelles. B, Misfolded proteins trigger a protective unfolded protein response (UPR). If this response is inadequate to cope with the level of misfolded proteins, it induces apoptosis.61Subcellular changes

AutophagyLisosomeAutophagy dan heterophagy

Smooth endoplasmic reticulumMassively enlarged

MitochondriaEnlarged Intracellular accumulation

Fatty liver. A, Schematic diagram of the possible mechanisms leading to accumulation of triglycerides in fatty liver. Defects in any of the steps of uptake, catabolism, or secretion can result in lipid accumulation. Downloaded from: StudentConsult (on 19 February 2012 10:23 PM)67

Fatty change of the liver. In most cells the well-preserved nucleus is squeezed into the displaced rim of cytoplasm about the fat vacuole.Downloaded from: StudentConsult (on 19 February 2012 10:23 PM) 2005 Elsevier 68

Cholesterolosis. Cholesterol-laden macrophages (foam cells, arrow) in a focus of gallbladder cholesterolosis.Downloaded from: StudentConsult (on 19 February 2012 10:23 PM) 2005 Elsevier 69

Protein reabsorption droplets in the renal tubular epithelium. Downloaded from: StudentConsult (on 19 February 2012 10:23 PM) 2005 Elsevier 70

Lipofuscin granules in a cardiac myocyte shown by light microscopyDownloaded from: StudentConsult (on 19 February 2012 10:23 PM) 2005 Elsevier 71

Lipofuscin granules in a cardiac myocyte shown by electron microscopy (note the perinuclear, intralysosomal location).Downloaded from: StudentConsult (on 19 February 2012 10:23 PM) 2005 Elsevier 72

Hemosiderin granules in liver cells. H+E stain showing golden-brown, finely granular pigment. Downloaded from: StudentConsult (on 19 February 2012 10:23 PM) 2005 Elsevier 73

Hemosiderin granules in liver cells. Prussian blue stain, specific for iron (seen as blue granules).Downloaded from: StudentConsult (on 19 February 2012 10:23 PM) 2005 Elsevier 74

Dystrophic calcification of the aortic valve. View looking down onto the unopened aortic valve in a heart with calcific aortic stenosis. It is markedly narrowed (stenosis). The semilunar cusps are thickened and fibrotic, and behind each cusp are irregular masses of piled-up dystrophic calcification. 2005 Elsevier 75ConclusionCell injury in the basis of any pathologic processesIt could be reversible or irreversible (ended with cell death)The morphological changes are so characteristicThe mechanism of cell injury should be beared in mind in your further study of BMD and medicineExam Questions on cell injuryhttp://peir2.path.uab.edu/bmp/article_6.shtml

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Mahmud Ghaznawie