cell1 injury ppt

7/28/2019 Cell1 Injury Ppt

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Cell Injury and Cell Death

Nirush Lertprasertsuke, M.D.Department of Pathology

Faculty of Medicine,

Chiang Mai University


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Cell I njury Normal cel l: homeostasis Sublethal injury: reversible injury I r reversible injuryCell death


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Normal homeostasis Genetic programs

metabolismdifferentiationspecialization

Constraints of neighboring cells Availability of metabotic

substrates


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Cellular Responses to Injury Acute cell injury

Reversible cell injury Cell death

Subcellular alterations in sublethal and

chronic injury Cellular adaptations: ~trophy/~plasia I ntracel lular accumulations Pathologic calcif ications

Cell aging


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Causes of cell injury Oxygen Deprivation: hypoxia/ischemia Physical agents Chemical agents and drugs I nfectious agents Immunologic reactions Genetic derangements Nutr itional imbalances: self-imposed


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Principles of cell injury Stimulus: type, duration, sever ity Cell: type, state, adaptabil i ty

Cellular targets

cell membranes: integritymitochondria: aerobic respiration cytoskeleton: protein synthesis cellular DNA: genetic apparatus

Structural and biochemical elements


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Molecular mechanisms (1)

ATP loss causes failure of biosynthesis

and ion pumps: cloudy swelling

Cytosolic free Ca is a potent destructiveagents: activates intracel lular enzymes and

causes cell death protein kinases: phosphorylation of protein phospholipases: membrane damage proteases: cytoskeletal disassembly


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Reactive oxygen metaboli tes (f ree radicals)

damage cells: O(-), OH (-), H2O2 peroxidation of l ipids (cel l memb.) thiol-containing protein damage (ion pump) DNA damage (protein synthesis) mitochondrial damage (Ca inf lux)

Membrane and cytoskeletal damage immune-mediated injury

Molecular mechanisms (2)


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Morphology of Reversible cell injury Ultrastructural damage to mitochondria

Low-amplitude swell ing (H igh-amplitude swell ing: irreversible)

Swell ing of cel lular organelles: hydropic

degeneration/cloudy swell ing Fatty change: sublethal impairment of

metabolism: l iver


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Morphology of Cell death Lysis: Disintegration of cel lular structure

followed by dissolution

Necrosis: spectrum ofmorphologicchanges that fol low cell death in living

tissue

Apoptosis:programmed cell death-elimination of unwanted host cel ls


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Necrosis Concurrent processes:

Enzymic digestion: lysis autolysis: lysosomes of the dead cells heterolysis: immigrant leukocytes

Denaturation of proteins I ntense eosinophil ia

Nonspecif ic DNA breakdown

Pyknosis Karyorhexis Karyolysis


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Patterns of Necrosis Coagulative necrosis L iquefactive necrosis Caseous necrosis Fat necrosis Gangrenous necrosis F ibr inoid necrosis


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Coagulative necrosis

Dead tissue: f irm and pale

I ntact c.outl ines and t.archi tecture I ntracellular acidosis denatures enzymesOcclusion of arter ial supply

Enzymes used in Dx of tissue damage Myocardium: CK (MB isoform), AST, LDH

Hepatocytes: ALT Str iated muscle: CK (MM isoform)

Exocrine pancreas: amylase


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Liquefactive necrosis Semi-l iquid viscous tissue Potent hydrolytic enzymes Examples

Hypoxic dead in the CNS: lysosomal enzymes

of the neurons and the relative lack of

extracellular structural protein

Bacter ial infection: pus

neutr ophi l hydrolases: acute inf lammation


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Caseous necrosis Soft and white: like cream cheese Amorphous eosinophi l ic mass, loss of

tissue archi tecture

Associated with granulomatousinf lammation(reaction) in Tuberculosis


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Fat necrosis Hard yellow-gray mater ial: fat tissue Examples:

Retroper itoneal fat necrosis associated with

acute of the pancreas

Traumatic fat necosis: breast, buttock


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Gangrenous necosis Mummif ied darkened and shr inkage Coagulative necrosis only or modif ied by

liquefactive necrosis Dry gangrene: l imb (lower leg/toe) Wet gangrene: hollow viscera (GI tract)

hemorrhage within the tissue


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Fibrinoid necrosis Deposits of f ibr in to the wall of necrotic

vessels Causes:

Vasculi tis: autoimmune disease

Hypertension


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ApoptosisSettings

During development Homeostatic mechanism to maintain cell

populations in tissue: involution

Defense mechanism e.g. immune reaction Injury

viral infection low doses of injur ious stimuli

Aging


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ApoptosisMechanisms

Signaling pathways Transmembrane signals: hormone, cytokines I ntracellular signaling: heat, viral infection

Control and integration stage: adaptor

proteins, Bcl-2, p53, granzyme B Execution phase: endonuclease activation,

catabolism of cytoskeleton Removal of dead cells


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Apoptosis


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ApoptosisBiochemical features

Protein Cleavages:cysteine proteases caspases:

nuclear scaffold

cytoskeletal proteins Protein cross-l inking: transglutaminase DNA breakdown: endonucleases

50~300 kb and then 180~200 bp Phagocytic recogni tion

phosphatidylserine

Apoptosis


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ApoptosisMorphology

Cell shr inkage Chromatin condensation Formation of cytoplasmic blebs and

apoptotic bodies Phagocytosis of apoptotic cel ls/bodies

Single cell or small clusters with intense

eosinophi l ic cytoplasm and dense

chromatin f ragments


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cell1 injury ppt

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