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MECHANISMSOFDISEASE Kajoke Avolonto Medic LearnCAUSESOFCELLINJURY ➤ Hypoxia ➤ Low oxygen ➤ Due to low oxygen in the blood (hypoxaemia) , low carrying capacity (anemia) or decreased blood flow (ischaemia) ➤ Inhibition of Ox. Phos. ➤ Chemical agents ad drugs ➤ Generate ROS2(O ) ➤ Hydroxyl ions are the most dangerous ➤ Disable Ox. Phos. (Cyanide) ➤ Infections ➤ Immune mediated processes ➤ Create endogenous self antigens ➤ Nutritional imbalances ➤ Excess or insufficiency ➤ Genetic ➤ Don’t make end product ➤ Side product made in excess ➤ Lack of enzymes ➤ Trauma ➤ Mechanical ➤ Extreme temperatures ➤ RadiationCHANGESINCELLINJURY ➤ Reversible ➤ Swelling of organelles and blebbing of plasma membrane ➤ Irreversible ➤ Breakdown of plasma membrane, organelles and nucleus ➤ Content leakage ➤ Irreversible nuclear changes ➤ Pyknosis ➤ Nuclei condense ➤ Karyorrhexis ➤ Nuclei fragment ➤ Karyolysis ➤ Nuclei dissolvePROTECTIONAGAINSTCELLINJURY ➤ Heat shock proteins helps maintain cell viability ➤ They prevent protein aggregation and label misfolded proteins for degradation ➤ Ex ubiquitinNECROSIS ➤ Main processes ➤ Denaturation of intracellular proteins ➤ Enzymatic digestionTYPESOFNECROSIS ➤ Coagulative ➤ Most common ➤ Due to protein denaturation ➤ Firm, pale wedge of tissue ➤ Liquefactive ➤ Seen in the brain and infections resulting in abscesses ➤ From degradation of tissues by enzymes ➤ Presence of pus (creamy yellow material with neutrophils) ➤ Caseous ➤ Cheese like ➤ Associated with TB ➤ Central necrosis ➤ Fat ➤ Caused by destruction of fat cells due to trauma or release of lipases from pancreatitis ➤ Causes fatty acids to react with calcium and forms white deposits in fatty tissue ➤ Injury to breast post car accident due to seatbelt ➤ Seen in pancreatitis ➤ See in some neonates post labour ➤ Fibrinoid ➤ Seen in immune reactions involving blood vessels ➤ Deposit of immune complexes and fibrin ➤ Seen in vasculitisINFARCT ➤ White infarct ➤ In solid organs ➤ End artery ➤ Wedge shape ➤ Common sites ➤ Heart, spleen and kidneys ➤ Red infarct ➤ Aka haemorrhagic infarct ➤ Dual blood supply to organs and ones with multiple anastomoses between capillary beds ➤ Organs with loose stomal tissue ➤ Haemmorhage from branching arteries and veinsGANGRENE ➤ Clinical term for visible necrosis ➤ Wet gangrene ➤Necrosis modified by bacteria ➤ Dry gangrene ➤Necrosis modified by air ➤ Gas gangrene ➤Necrosis modifies by gas forming bacteriaAPOPTOSIS ➤ Energy dependent cell death ➤ Selective (non random) ➤ No inflammatory response ➤ Can be physiological or pathological ➤ Inhibited by growth factors, extracellular matrix (ECM), sex steroids, etc ➤ Induced by growth factor , loss of ECM attachment, glucocorticoids, etc ➤ Mechanism ➤ Extrinsic pathway by external death receptors (TNF of Pas receptors) ➤ Intrinsic pathway by withdrawal of growth factor ➤ Macrophages or histiocytes then phagocytose apoptotic cellsINTRACELLULARACCUMULA TION ➤ Water and electrolytes ➤ Lipids ➤ Carbohydrates ➤ Proteins ➤ PigmentsACUTEINFLAMMATION ➤ Protective response of living tissue to injury ➤ Rapid ➤ Short lived ➤ Innate ➤ StereotypedWHATIMMUNECELLISPREDOMINANTINACUTEINFLAMMA TION? ➤ NeutrophilsCLINICALFEATURES ➤ Heat ➤ Redness ➤ Pain ➤ Loss of function ➤ SwellingKEYFEA TURES ➤ Vascular reaction ➤ Transient vasoconstriction ➤ Followed by vasodilation increasing blood flow ➤ Exudation of fluid into tissues due to increased vascular permeability ➤Hydrostatic pressure ➤ hOUTdrostatic ➤Osmotic pressure ➤ OsmotIN ➤ Vascular stasis ➤ Cellular reaction ➤ Infiltration of inflammatory cells ➤Mainly neutrophils ➤ Opsonization for phagocytosis done by C3b and IgGEXUDATEVSTRANSUDA TE ➤ Exudate: high protein content ➤ Purulent (meningitis) ➤ Hemorrhagic (malignancies) ➤ Serous (blisters) ➤ Fibrinous (fibrinous pericarditis) ➤ Transudate: low protein contentNEUTROPHILEXTRAVASA TION ➤ Margination ➤ Rolling ➤ Adhesion ➤ DiapedesisWHATIMMUNECELLSAREASSOCIA TEDWITHVIRALINFECTIONS ➤ LymphocytesKILLINGMECHANISMS ➤ Oxygen dependent ➤ Free radicals released into phagosome ➤ Respiratory burst ➤ Oxygen independent ➤ By enzymes ➤Lysozymes, proteases and nucleases ➤ Punch holes in bacterial wallANTI-INFLAMMATORY ➤ Aspirin ➤ Antihistamines ➤ Corticosteroids ➤ Leukotriene antagonist ➤ NSAIDS ➤ TNF alpha antagonistCHRONICINFLAMMA TION ➤ May take over from acute inflammation ➤ May arise gradually with an obvious acute phase ➤ Contains macrophages ➤Mastermind of chronic inflammation ➤For phagocytosis, antigen presentation and control of other cellsGIANTCELLSVSGRANULOMA ➤ Giant cell ➤ Fused macrophages ➤ Langhans giant cell (TB) ➤ Foreign boy type ➤ outon type giant cell (xanthoma & fat necrosis) ➤ Granuloma ➤ Modified macrophages ➤ Epitheliod, slipper shaped ➤ Foreign body granulomas ➤ Immune granulomas ➤ Caseating granulomas (TB)EFFECTSOFCHRONICINFLAMMA TION ➤ Fibrosis - chronic cholecystitis ➤ Impaired function - liver cirrhosis, IBD ➤ Increased function - thyrotoxicosis ➤ Atrophy - autoimmune gastritis ➤ Inappropriate stimulation of immune response - atopic disease (asthma, eczema, hay fever)PRINCIPLEOFWOUNDHEALING ➤ Close the gap ➤ Repair with a scar the smaller the betterPROCESSESINVOLVED ➤ Haemostasis ➤ Inflammation ➤ Regeneration or repair ➤ Primary intension ➤Complete resolution ➤Clean wound brought together ex. with stitches ➤ Secondary intension ➤No complete resolution ➤Excision wound, infected wounds, etc.TISSUEREGENERATION ➤ Labile ➤ Constantly ➤ Haematopoeitic tissue ➤ Stable ➤ When necessary ➤ Liver parenchyma ➤ Permanent ➤ No ability to regenerate ➤ Neural tissueREGENERATIONVSFIBROUSSCAR ➤ Regeneration ➤Repair is complete ➤The damage is in labile or stable tissue ➤The damage is not extensive ➤ Fibrous repair ➤The healing with the formation of a scar ➤Healing by secondary intension ➤When significant tissue is lost ➤If permanent tissue is injuredGRANULATIONTISSUE ➤ Not a granuloma ➤ Made of capillaries, fibroblasts, myofibroblasts and inflammatory cells ➤ Fills the gap ➤ Provides oxygen and nutrients ➤ Pulls edges together ➤ Cells involved ➤Inflammatory cells ➤Endothelial cells ➤Fibroblasts and myofibroblastsFACTORSTHA TINFLUENCEHEALING ➤ ype ➤ Size ➤ Location ➤ Blood supply ➤ Infection ➤ Foreign bodies ➤ Age ➤ Obesity ➤ Diabetes ➤ Drugs ➤ Vitamin deficiencyCOMPLICATIONSOFFIBROUSREPAIR ➤ Insufficient fibrosis ➤ Formation of adhesions ➤ Loss of function (ex post MI) ➤ Overproduction of fibrous scar tissue (keloid) ➤ Excessive scar contractionBONEHEALING ➤ Haematoma ➤ Soft callus ➤ No calcium ➤ Made of cartilage that woven bone forms in ➤ Hard callus ➤ RemodellingHAEMOST ASIS ➤ Complex that stops bleeding ➤ Coagulation cascade ➤ Need balance between pro-thrombic and anti-thrombic state ➤ 3 stages ➤ Unstable platelet plug ➤ Platelets adheon Willebrand Factor in subendothelial structures then aggregate and form a plug held together by fibrin ➤Stabilisation of plug with fibrin ➤Dissolution ➤ Components ➤ Vessel wall ➤Platelets ➤Coagulation system ➤Fibrinolytic systemCOAGULATIONCASCADE ➤ Intrinsic pathway ➤ Damage to endothelial lining of blood vessels activating factor XII ➤ Extrinsic pathway ➤ rauma releases tissue factor III ➤COAGULA TIONINHIBITORS ➤ Anti-thrombin III ➤ Inhibit thrombin and 10a ➤ Protein C ➤ Cleave co factoa and VIIIa ➤ Protein SFIBRINOLYSIS ➤ T-PA ➤ Streptokinase ➤ UrokinaseHAEMOPHILIA ➤ Spontaneous internal bleeding ➤ Inherited deficiency of factor 8 ➤ Often bleed around jointsTESTOFHAEMOST ASIS ➤ Prothrombin time (PT) - extrinsic pathway ➤ Factors II, VII, X and fibrinogen ➤ Activated partial thromboplastin time (APTT) - intrinsic pathways ➤ II,, VIII, IX, X, XI and fibrinogenWARFARIN ➤ Vitamin K antagonist ➤ Inhibit factors II, VII, IX, X (1972) ➤ If start bleeding ➤Vitamin K ➤Prothrombin complex concentrateTHROMBOSIS ➤ The formation of a solid mass of blood clot in the circulatory system ➤ Virchow’s triad ➤ Prothrombic states ➤ Stasis + blood constituents —> venous ➤ Blood constituents and vessel wall —> arterialWHATISAVTE ➤ erm for DVT and PERISKFACTORSOFVTE ➤ Age ➤ Previous VTE ➤ OCP/HRT ➤ Smoking ➤ Obesity ➤ Immobility ➤ Post-opRISKFACTORSFORARTERIALTHROMBOSIS ➤ Age ➤ Smoking ➤ Atherosclerosis ➤ Hypertension ➤ Hypercholesterolaemia ➤ DiabetesHOWWOULDALEGLOOKDIFFERENTBETWEENDVTANDARTERIALTHROMBOSIS ➤ DVT: hot red and painful ➤ Arterial thrombosis: cold and paleOUTCOMESOFTHROMBOSIS ➤ Propagation ➤ Lysis ➤ Embolism ➤Blockage of a vessels by a liquid, solid or gas at a site distant from its origin ➤Most emboli and thrombo-emboli ➤PE ➤ Massive PE > 60% reduction ➤ Haemodynamic compromise ➤ Major PE: medium size vessels blocked ➤ Shortness of breath, pleuritic chest pain, haemoptysis ➤ Minor PE: small peripheral pulmonary arteries blocked ➤ Asymptomatic or minor shortness of breath ➤ Recurrent PEs lead to pulmonary hypertension ➤ Organisation ➤ RecanalisationA THEROSCLEROSIS ➤ Thickening, narrowing and hardening of walls of large and medium sized arteries due to atheroma (accumulation of lipids in intima and media of large and medium sized arteries) ➤ Development ➤ Fatty streak ➤ Lipid deposit in intima ➤ No disturbance to blood flow ➤ Slightly raised ➤ Simple plaque ➤ Raised ➤ ~ 1cm in diameter ➤ Often around ostia (branch point in vessels) ➤ Impinge on vessel lumen ➤ Complicated plaque ➤ Calcification ➤ Ulceration ➤ Thrombosis ➤ HaemorrhageMICROAPPEARANCEOFA THEROSCLEROSIS ➤ Early changes ➤ Accumulation of foam cells (combination of smooth muscle cells, macrophages and fat cells) ➤ Proliferation of smooth muscle cells ➤ Extracellular lipid deposit ➤ Scattered T lymphocytes ➤ Later changes ➤ Fibrosis ➤ Necrosis ➤ Calcification ➤ Disruption of internal elastic lamina ➤ Damage going into media ➤ Plaque fissuring and rupture —> clot ➤ Weakening of vessel wall leading to aneurysm and ruptureCELLULAREVENTSLEADINGUPTOA THEROSCLEROSIS ➤ Chronic endothelial injury ➤ Endothelial dysfunction ➤ Smooth muscle emigration from media to intima ➤ Production of foam cells ➤ Smooth muscle proliferation in response to cytokines and growth factors ➤ Collagen and matrix deposition ➤ NeovascularisationCELLSINVOLVED ➤ Endothelial cells ➤ Platelets ➤ Smooth muscle cells ➤ Macrophages ➤ Lymphocytes ad neutrophils (minor)RISKFACTORS ➤ Age ➤ Gender ➤ Women protected until menopause ➤ Hyperlipidaemia ➤ Smoking ➤ Hypertension ➤ Alcohol ➤ DiabetesTYPESOFCELLULARADAPT A TION ➤ Regeneration ➤ Replacement of cells lost by identical cells ➤ Tissue size stays the same ➤ Reconstitution ➤ Replacement of a lost part if the body (minimal in mammals) ➤ Hyperplasia ➤ Increase in tissues or organ size due to increased cell numbers ➤ Hypertrophy ➤ Increase in tissue or organ size due to increased cell size ➤ Atrophy ➤ Shrinkage of a tissue or organ size due to a decrease in size and/or number of cells ➤ Denervation atrophy ➤ Disuse atrophy ➤ Metaplasia ➤ Reversible change of one differentiated cell type to another ➤ Can lead to dysplasia ➤ Aplasia ➤ Failure of a specific tissue or organ to develop ➤ Hypoplasia ➤ Underdevelopment/incomplete development of a tissue or organ ➤ Dysplasia ➤ Abnormal maturation of cells in a tissue (diff definitions in pathology)