Cell InjuryMahmud GhaznawieDept of PathologyHasanuddin University

Membran plasmaNukleus

Aparatus golgiMitokondriaLisosom & peroksisom

The smooth endoplasmic reticulumThe rough endoplasmic reticulum

Cytoskeleton

MikrotubulesActin filamentsIntermediate filaments

Cell Injury Stressed so severely, cant adapt further Exposed to inherently damaging agents * Reversible or irreversible * Outcome depends onType, duration and severity of injuryType, state, and adaptability of cell

Cellular Adaptation to StressHypertrophyHyperplasiaAtrophyMetaplasia

Cellular Adaptation to StressHypertrophy

Cellular Adaptation to StressPhysiologic hyperplasiaHormonal hyperplasiaCompensatory hyperplasiaPathologic hyperplasiaExcessive hormon stimulationPapilloma (virus)Keloidetc

Cellular Adaptation to StressAtrophy

Cellular Adaptation to StressMetaplasia

Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 3 March 2006 10:56 PM) 2005 Elsevier

Oxygen (too much or too little)Physical agents (trauma, temp, pressure, electric shock)Chemical agents (CN-, Hg, O3, CO, EtOH, drugs, ROS)Infectious agents (viruses, bacteria, fungi)Immunologic reactions (anaphylaxis, autoimmune diseases)Genetic defects (Sickle cell disease, Down synd, Tay-Sachs)Dietary (vitamins def/xs, malnutrition, xs calories)

Agents of cell injury

Mechanisms of cellular injuryATP depletionMitochondrial damageIncreased cytosolic CaIncreased ROS productionMembrane damage

Mechanisms of cellular injuryATP depletion

Mechanisms of cellular injury

Mechanisms of cellular injuryIncrease of cytosolic Ca

Mechanisms of cellular injuryIncreased ROS production

Mechanisms of cellular injuryMembrane damage

Important targets of injuryMitochondria (aerobic respiration; apoptotic signals)Membranes (cell and subcellular organelles)Protein synthesis machineryCytoskeletonGenetic apparatus (DNA)

Oxygen Too much via ROS productionToo little viaHypoxiadecreased O2 content of bloodIschemiainadequate blood flow (compromises delivery of nutrients and removal of wastes)NB: ischemia worse than hypoxia

Agents of cell injury

Reactive Oxygen Species (ROS)Have unpaired electron (most)Very-to-Extremely reactiveNon-specific Self propagatingReferred to as ROS, ROM, free radicalsUsually damaging (2 exceptions)

Major ROSSuperoxide (O2.-)Hydrogen peroxide (H2O2)Hydroxyl radical (HO.)Nitric oxide (NO.)

Sources of ROSUV light, ionixing radiationMitochondrial ETSEnzymes (P450, XO, NADPH oxidase)Reduced metals (Fe, Cu, etc)NB: Fenton reaction

Effects/Targets of ROSMembranes (lipid peroxidation)Proteins (via SH, TRP and TYR ox, etc)Cross linking; fragmentationDNA damageStrand breakage, T-T dimers

Cellular defenses against ROS(Antioxidants)EnzymaticSOD, catalase, GPXNon-enzymaticVitamins A, C, EGlutathione (GSH)Metal binding proteins (transferrin, ceruloplasmin, etc)NB: lipid and water soluble species

Example of Cell Injury and Necrosis Ischemia-reperfusion injuryMyocardial infarctStroke

Ischemia-reperfusion Injury

Ischemia-reperfusion injury

Ischemia-reperfusion InjuryATP

ADP

AMP

Adenosine

Inosine

HypoxanthineUric Acid + SuperoxideXDHXOO2ReperfusionCa-activated proteaseReperfusionPMNs

Morphology of cell injurySwelling (via increased water content)Fatty change (steatosis, TG)Necrosis (dead cells)Intracellular deposits (lipid, CHO, protein)Loss of cellular fine structure (microvilli)Karyolysis (DNA degradation)Pyknosis (nuclear shrinkage)Karyorrhexis (nuclear fragmentation)

Morphology of cell injury

Reversible vs irreversible cell injury Reversible injuryDecreased ATP levelsIon imbalanceSwelling Decreased pHFatty change (liver)

Irreversible injuryAmorphous densities in mitochondriaSevere membrane damageLysosomal ruptureExtensive DNA damage

Subcellular response to injuryLysosomes (heterophagy; autophagy)Smooth ER (induction)Mitochondria (D number, size and shape)Cytoskeleton (D phagocytosis, locomotion)Nucleus (karyolysis, karyorrhexis, pyknosis)Membranes (cellular and subcellullar)

Electron micrograph of a normal epithelial cell of the proximal kidney tubule. Note abundant microvilli (mv) lining the lumen (L). Epithelial cell of the proximal tubule showing reversible ischemic changes. The microvilli (mv) are lost and have been incorporated in apical cytoplasm; blebs have formed and are extruded in the lumen (L). Mitochondria are slightly dilated. (Compare with A.)

Irreversibly Injured cellDead cellApoptosisNecrosis

Cell size Enlarged Reduced

NucleusPyknosis/karyorrhexis/karyolysisFragmentation

Plasma membraneDisruptedIntact

Cellular contentsEnzymatic digestionIntact

InflammationFrequentNone

Physiologic/pathologic Pathologic PhysiologicTable 1-2. Features of Necrosis and Apoptosis Feature Necrosis ApoptosisApoptosis dibahas pada kuliah Prof. Irawan Yusuf

NecrosisCoagulativeLiquefactiveCaseousFatGangrenousFibrinoid

Coagulative necrosisPreservation of structureFirm Protein denaturationHypoxic tissue death (except brain)

Liquefactive necrosisEnzymatic digestionAutolysis + WBCLiquid, viscous massMay contain pusBacterial infections (via inflammation)Hypoxic brain injury

Caseous necrosisSubset of coagulative necrosisTBCheesy, white Surrounded by inflammatory cells (granulomatous reaction)Complete destruction of tissue Caseous necrosis is just a combination of coagulative and liquefactive necrosis

Confluent cheesy tan granulomas in the upper portion of this lung in a patient with tuberculosisCaseous necrosis

Fat necrosisNot a specific patternFocal areas of fat digestionUsually via release of lipases from pancreasFFA combine with Calcium to produce soapsAppear grossly as the soft, chalky white areas

Fibrinoid necrosis

Intracellular AccumulationsLipids (TG and Cholesterol)ProteinsPigmentsGlycogen (genetic disease)

Fatty change (steatosis)Normal liver

Mallory bodies (the red globular material) composed of cytoskeletal filaments in liver cells chronically damaged from alcoholism. These are a type of "intermediate" filament between the size of actin (thin) and myosin (thick).

Cholesterolosis. Cholesterol-laden macrophages (foam cells) from a focus of gallbladder cholesterolosis (arrow).

Protein reabsorption droplets in the renal tubular epithelium

Lipofuscin granules in a cardiac myocyteA. Light microscopy (deposits indicated by arrows) B. Electron microscopy (note the perinuclear, intralysosomal location)

Hemosiderin granules in liver cellsH&E section showing golden-brown, finely granular pigmentPrussian blue reaction, specific for iron.

Calcification

Mahmud Ghaznawie

Go to slide 31 form hereNormal cell has relative narrow range of functions and structureLimited changes in metabolism = homeostasis (increased Glc and TG metabolism in active contracting muscle)Stress = demands in excess of normal homeostatic changes leads to adaptationsIf stress exceeds adaptive response of cell - injuryIn addition, a variety of agents can directly injure cells (ie CN, , Hg, pH, temp, etc)The sequential ultrastructural changes seen in necrosis (left) and apoptosis (right). In apoptosis, the initial changes consist of nuclear chromatin condensation and fragmentation, followed by cytoplasmic budding and phagocytosis of the extruded apoptotic bodies. Signs of cytoplasmic blebs, and digestion and leakage of cellular components.

Mallory Bodies