Today’s Quranic verse

But to those who believe and do deeds of righteousness, He will give their (due) rewards, and more, out of His bounty: But those who are disdainful and arrogant, He will punish with a grievous penalty; Nor will they find, besides God, any to protect or help them. [004:173] 

Today’s Quranic verse

CELL INJURYCELL INJURY

Principles of Cell InjuryPrinciples of Cell Injury

• Dependent upon the etiology, duration, and severity of the Dependent upon the etiology, duration, and severity of the inciting injuryinciting injury

• Dependent upon cell type, stage of cell cycle, and cell Dependent upon cell type, stage of cell cycle, and cell adaptabilityadaptability

• Cellular membranes, mitochondria, endoplasmic reticulum, Cellular membranes, mitochondria, endoplasmic reticulum, and the genetic apparatus are particularly vulnerableand the genetic apparatus are particularly vulnerable

• Injury at one focus often has a cascade effectInjury at one focus often has a cascade effect

• Morphologic reactions occur only after Morphologic reactions occur only after criticalcritical biochemical biochemical (molecular) damage(molecular) damage

Normal cell is in a steady state “Homeostasis”

Change in Homeostasis due to stimuli - Injury

Response to Injury – Reversible (adaptation)/ Irreversible (cell death)

Adaptive Responses: Adaptive Responses: – AtrophyAtrophy– HypertrophyHypertrophy– HyperplasiaHyperplasia– MetaplasiaMetaplasia

Reversible vs. Irreversible InjuryReversible vs. Irreversible Injury

Cell injury is a continuum, and it is not possible to identify Cell injury is a continuum, and it is not possible to identify the exact point at which injury becomes irreversible.the exact point at which injury becomes irreversible.

However, some ultrastructural and light microscopic However, some ultrastructural and light microscopic

changes are associated with each form of injury. changes are associated with each form of injury.

Once an irreversible injury occurs, the cell undergoes Once an irreversible injury occurs, the cell undergoes necrosis, which is the necrosis, which is the light-microscopic hallmarklight-microscopic hallmark of cell of cell death.death.

In general, permanent organ injury is associated with the In general, permanent organ injury is associated with the death of individual cells. death of individual cells.

By contrast, the cellular response to persistent sub-lethal By contrast, the cellular response to persistent sub-lethal injury, whether chemical or physical, reflects adaptation of injury, whether chemical or physical, reflects adaptation of the cell to a hostile environment. These changes are, for the the cell to a hostile environment. These changes are, for the most part, reversible on discontinuation of the stress”most part, reversible on discontinuation of the stress”

If the acute stress to which a cell must react exceeds its If the acute stress to which a cell must react exceeds its ability to adapt, the resulting changes in structure and ability to adapt, the resulting changes in structure and function lead to the death of the cellfunction lead to the death of the cell

Causes of Cell InjuryCauses of Cell Injury• HypoxiaHypoxia• Physical agents including Radiations Physical agents including Radiations • Chemicals and DrugsChemicals and Drugs• Microbiologic AgentsMicrobiologic Agents• Immunologic ReactionsImmunologic Reactions• Genetic DefectsGenetic Defects• Nutritional ImbalancesNutritional Imbalances

Mechanisms of Cell InjuryMechanisms of Cell Injury

Mechanisms of Cell InjuryMechanisms of Cell Injury• Ischemia/HypoxiaIschemia/Hypoxia• Activated Oxygen Species(OActivated Oxygen Species(O22

.-.-, H, H22OO22, OH, OH.. ) )– RadiationRadiation– InflammationInflammation– Oxygen toxicityOxygen toxicity– ChemicalsChemicals– Reperfusion injuryReperfusion injury

OthersOthersChemicalsChemicalsInfectious agentsInfectious agentsMechanical disruptionMechanical disruptionDeficiency of essential metabolitesDeficiency of essential metabolitesDamage to DNADamage to DNA

MECHANISMS OF CELL INJURYMECHANISMS OF CELL INJURY

ISCHEMIC AND HYPOXIC ISCHEMIC AND HYPOXIC INJURYINJURY

Reversible InjuryReversible Injury

- - Decreased oxidative phosphorylationDecreased oxidative phosphorylation

• reduced ATPreduced ATP increased cytosolic free calciumincreased cytosolic free calcium

• reduced activity of “sodium pump”reduced activity of “sodium pump” accumulation of sodium by cellaccumulation of sodium by cell is-osmotic gain of water (swelling)is-osmotic gain of water (swelling) diffusion of potassium from celldiffusion of potassium from cell

- - Increased Cytosolic Calcium (activates enzymes)Increased Cytosolic Calcium (activates enzymes)

• ATPaseATPase decreased ATPdecreased ATP

• PhospholipasePhospholipase decreased phospholipidsdecreased phospholipids

• EndonucleaseEndonuclease nuclear chromatin damagenuclear chromatin damage

• ProteaseProtease disruption of membrane and cytoskeletal proteinsdisruption of membrane and cytoskeletal proteins

-- Increased anaerobic glycolysisIncreased anaerobic glycolysis

• glycogen depletionglycogen depletion• lactic acid accumulationlactic acid accumulation• accumulation of inorganic phosphatesaccumulation of inorganic phosphates• reduced intracellular pHreduced intracellular pH

- - Detachment of ribosomesDetachment of ribosomes• reduced protein synthesisreduced protein synthesis

- - Worsening mitochondrial functionWorsening mitochondrial function

- - Increasing membrane permeabilityIncreasing membrane permeability

- - Cytoskeleton dispersionCytoskeleton dispersion• loss of microvilliloss of microvilli• formation of cell surface blformation of cell surface blebsebs

Reversible Injury results inReversible Injury results in– Swelling of mitochondria, endoplasmic Swelling of mitochondria, endoplasmic

reticulum, and entire cellsreticulum, and entire cells

Irreversible InjuryIrreversible Injury

– Mitochondrial changesMitochondrial changes• severe vacuolizationsevere vacuolization• amorphous calcium-rich densitiesamorphous calcium-rich densities

– Extensive plasma membrane damageExtensive plasma membrane damage– Prominent swelling of lysosomesProminent swelling of lysosomes– Massive influx of calcium (on reperfusion)Massive influx of calcium (on reperfusion)– Continued loss of cell proteins, coenzymes, Continued loss of cell proteins, coenzymes,

ribonucleic acids and other metabolitesribonucleic acids and other metabolites– Leakage of enzymes measured in serumLeakage of enzymes measured in serum

– Injury to lysosomal membranesInjury to lysosomal membranes• leakage of degradative enzymesleakage of degradative enzymes

– activation of acid hydrolases due to reduced intracellular activation of acid hydrolases due to reduced intracellular pH with degradation of cell componentspH with degradation of cell components

– Prominent leakage of cellular enzymes Prominent leakage of cellular enzymes – Influx of macromolecules from Influx of macromolecules from

interstitiuminterstitium– ““Myelin figures”-whorled phospholipid Myelin figures”-whorled phospholipid

massesmasses

FREE RADICAL MEDIATION OF CELL FREE RADICAL MEDIATION OF CELL INJURYINJURY

• Free Radical Injury Contributes to:Free Radical Injury Contributes to:– Chemical and radiation injuryChemical and radiation injury– Oxygen and other gaseous toxicityOxygen and other gaseous toxicity– Cellular agingCellular aging– Microbial killing by phagocytic cellsMicrobial killing by phagocytic cells– Inflammatory damageInflammatory damage– Tumor destruction by macrophagesTumor destruction by macrophages– OthersOthers

• Definition Of Free RadicalsDefinition Of Free Radicals– Extremely unstable, highly reactive chemical Extremely unstable, highly reactive chemical

species with a single unpaired electron in an outer species with a single unpaired electron in an outer orbitalorbital

• Examples Of Free RadicalsExamples Of Free Radicals– OHOH.., H, H.., O, O22

.-.-

• Source of Free RadicalsSource of Free Radicals– Hydrolysis of water into OHHydrolysis of water into OH.. and H and H.. by ionizing by ionizing

radiationradiation– Redox reactions in normal physiologyRedox reactions in normal physiology

• respirationrespiration• intracellular oxidase actionintracellular oxidase action• transition metal reactionstransition metal reactions

– Metabolism of exogenous chemicalsMetabolism of exogenous chemicals

• Free Radical Injury MechanismsFree Radical Injury Mechanisms

– Lipid peroxidation of membranesLipid peroxidation of membranes• double bonds in polyunsaturated lipidsdouble bonds in polyunsaturated lipids

– Lesions in DNALesions in DNA• reactions with thymine with single-strand breaksreactions with thymine with single-strand breaks

– Cross-linking of proteinsCross-linking of proteins• sulfhydryl-mediated protein cross-linkingsulfhydryl-mediated protein cross-linking

• Free Radical DegradationFree Radical Degradation

– Unstable with spontaneous decayUnstable with spontaneous decay

– Decay accelerated byDecay accelerated by• superoxide dismutasesuperoxide dismutase• glutathioneglutathione• CatalaseCatalase

– Antioxidants (vitamin E, ceruloplasmin)Antioxidants (vitamin E, ceruloplasmin)• block formation or scavenge block formation or scavenge

CHEMICAL INJURYCHEMICAL INJURY

Can cause:Can cause:•       •       Injury to cell membrane and other cell Injury to cell membrane and other cell

structuresstructures•       •       Block enzyme pathways (e.g cyanide)Block enzyme pathways (e.g cyanide)•       •       Coagulate cell proteinsCoagulate cell proteins•       •       Upset concentration gradients and pHUpset concentration gradients and pH

Direct action or Conversion to reactive toxic metaboliteDirect action or Conversion to reactive toxic metabolite

RADIATION INJURYRADIATION INJURY

Causes:Causes:

Immediate cell deathImmediate cell deathInteruption of cell replication (cancer cells)Interuption of cell replication (cancer cells)Mutation (thymidine dimers)Mutation (thymidine dimers)Non-ionizing radiations can cause thermal injuryNon-ionizing radiations can cause thermal injury

BIOLOGICAL AGENTS CAUSING INJURYBIOLOGICAL AGENTS CAUSING INJURY

Viral injuryViral injury• Direct cytotoxicityDirect cytotoxicity• Indirect cytotoxicity, via the immune system Indirect cytotoxicity, via the immune system

(activated killer T cells identify viral proteins on the (activated killer T cells identify viral proteins on the cell surface and kill the cell)cell surface and kill the cell)

Bacterial injuryBacterial injury• Mostly due to their metabolic products & secretionsMostly due to their metabolic products & secretions• Host inflammatory reactionHost inflammatory reaction