CELL DEATHCELL DEATH

•Swelling, denaturation and coagulation Swelling, denaturation and coagulation

of proteinsof proteins•Breakdown of cellular organellesBreakdown of cellular organelles•Cell ruptureCell rupture

Common type of necrosis after Common type of necrosis after exogenous stimuli.exogenous stimuli.

NECROSISNECROSISThe sum of the morphologic changesThe sum of the morphologic changes that follow cell death in living tissuethat follow cell death in living tissue and organ:and organ:

• Denaturation of proteins.• Enzymatic digestion of organelles and cytosol.

• Enzymatic digestion by lysosomal Enzymatic digestion by lysosomal enzymes of the dead cells enzymes of the dead cells themselves.themselves.

AUTOLYSISAUTOLYSIS

HETEROLYSISHETEROLYSIS

• Digestion by lysosomal enzymes of Digestion by lysosomal enzymes of immigrant leukocytes.immigrant leukocytes.

Three pattern of nuclear Three pattern of nuclear changeschanges

Karyolysis (DNase activity)Karyolysis (DNase activity)

Pyknosis (DNA condensation)Pyknosis (DNA condensation)

Karyorrhexis (fragmentationKaryorrhexis (fragmentation

of pyknotic nucleus)of pyknotic nucleus)

Morphologic appearance of necrosisMorphologic appearance of necrosis

• Increased eosinophilia:Increased eosinophilia: Loss of RNA in the cytoplasm Loss of RNA in the cytoplasm Increased binding of eosin to denatured Increased binding of eosin to denatured

cytoplasmiccytoplasmic protein protein • More glassy homogeneous appearance More glassy homogeneous appearance Loss of glycogen particlesLoss of glycogen particles• Vacuolated and moth-eaten cytoplasmVacuolated and moth-eaten cytoplasm• Calcification of necrotic cellsCalcification of necrotic cells

TYPES OF CELL DEATHTYPES OF CELL DEATH• necrosisnecrosis Coagulation necrosisCoagulation necrosis

Caseous necrosisCaseous necrosis

GangreneGangrene

Liquefaction necrosis( fat necrosis)Liquefaction necrosis( fat necrosis)

Fibrinoid necrosisFibrinoid necrosis

• ApoptosisApoptosis

Coagulation necrosisCoagulation necrosis

Denatures of both structural and Denatures of both structural and

enzymatic proteins by injury or the enzymatic proteins by injury or the

subsequent increasing intracellular subsequent increasing intracellular

acidosis.acidosis.

Caseous necrosisCaseous necrosisA subtype of coagulation necrosisA subtype of coagulation necrosisWhite and cheesyWhite and cheesyTuberculosisTuberculosisCompletely obliterated tissue Completely obliterated tissue architecturearchitecture

GangreneGangreneA subtype of coagulation necrosisA subtype of coagulation necrosis

Dry gangreneDry gangrene

Wet gangreneWet gangrene

Gas gangreneGas gangrene

Liquefactive necrosisBacterial or fungal infections

Central nervous system

Amebiasis

Fat necrosisTraumatic

Activated pancreatic lipases

Fibrinoid degeneration Deeply eosinophilic

• Collagen diseases• Necrotic vasculitis• Malignant hypertension

APOPTOSIS (Programmed cell death)

• Programmed destruction of cells during Programmed destruction of cells during embryogenesis.embryogenesis.• Hormone dependent involution of tissues Hormone dependent involution of tissues in the adult.in the adult.• Cell deletion in proliferating cell popula- Cell deletion in proliferating cell popula- tions (intestinal crypt epithelium), tions (intestinal crypt epithelium), tumors, and lymphoid organs.tumors, and lymphoid organs.

• Pathologic atrophy in parenchymal Pathologic atrophy in parenchymal

organs after duct obstruction.organs after duct obstruction.• Cell death by cytotoxic T cells.Cell death by cytotoxic T cells.• Cell injury in certain viral diseases.Cell injury in certain viral diseases.• Cell death produced by a variety of Cell death produced by a variety of

injurious stimuli given in low dosesinjurious stimuli given in low doses

(e.g. mild thermal injury).(e.g. mild thermal injury).

MORPHOLOGICAL FEATURES MORPHOLOGICAL FEATURES OF APOPTOSISOF APOPTOSIS

• Cell shrinkageCell shrinkage• Chromatin condensation and fragmentation.Chromatin condensation and fragmentation.• Formation of cytoplasmic blebs and apoptoticFormation of cytoplasmic blebs and apoptotic bodies.bodies.• Phagocytosis of apoptotic bodies by adjacent Phagocytosis of apoptotic bodies by adjacent healthy cells or macrophages.healthy cells or macrophages.• Lack of inflammation.Lack of inflammation.

NecrosisNecrosis ApoptosisApoptosisStimuliStimuli Hypoxia Physical Hypoxia Physical Toxins PathologicalToxins PathologicalHistologyHistology Cell swelling Single cell Cell swelling Single cell Coagulation N ChromatinCoagulation N Chromatin Disruption of condensationDisruption of condensation organelles Apoptotic bodiesorganelles Apoptotic bodiesDNADNA Random Internucleosomal Random Internucleosomalbreakdownbreakdown Diffuse Diffuse

NecrosisNecrosis ApoptosisApoptosis

Mechanism Mechanism ATP depletion Gene activation ATP depletion Gene activation

Membrane EndonucleaseMembrane Endonuclease

injuryinjury

Free radicalsFree radicals

Tissue Tissue Inflammation No inflammation Inflammation No inflammation

reactionreaction Phagocytosis of Phagocytosis of

apoptotic bodiesapoptotic bodies

• Fig 1-18

Biochemical features of apoptosisBiochemical features of apoptosis

1.PROTEIN CLEAVAGE:1.PROTEIN CLEAVAGE: Caspases (cysteine protease)Caspases (cysteine protease) Nuclear scaffoldNuclear scaffold Cytoskeletal proteinCytoskeletal protein2.PROTEIN CROSS-LINKING:2.PROTEIN CROSS-LINKING: TransglutaminaseTransglutaminase Cytoplasmic proteinCytoplasmic proteinshrunken shallsshrunken shalls apoptotic bodiesapoptotic bodies Biochemical features of apoptosisBiochemical features of apoptosis

3. DNA breakdown:3. DNA breakdown: 50-300 kb pieces 50-300 kb pieces Ca2+, Mg2+ dependent endonucleasesCa2+, Mg2+ dependent endonucleases DNA oligonucleosomesDNA oligonucleosomes DNA ladders (also seen in necrosis)DNA ladders (also seen in necrosis)4. PHAGOCYTIC RECOGNITION4. PHAGOCYTIC RECOGNITION Receptors on macrophages for the Receptors on macrophages for the surface components surface components (phosphatidylserine, thrombospondin) (phosphatidylserine, thrombospondin) on apoptotic bodies.on apoptotic bodies.

• Fig 1-19

• Apoptosis-associated genesApoptosis-associated genes

bcl-2, c-myc, p53bcl-2, c-myc, p53

• Fig 1-20

• AbsorptionAbsorption• Discharge: Erosion UlcerDischarge: Erosion Ulcer Sinus Fistula CavitationSinus Fistula Cavitation• OrganizationOrganization• EncapsulationEncapsulation• CalcificationCalcification

Fates of necrosisFates of necrosis

Regeneration:Regeneration:Completely regenerationCompletely regenerationFibrous repairFibrous repair

Chapter ThreeChapter Three RepairRepair

Section ASection A

• Labile cellsLabile cells• Stable cellsStable cells• Permanent cellsPermanent cells

Regeneration capacityRegeneration capacity

1. Cell-cell interaction1. Cell-cell interaction Conditioned mediumConditioned medium Contact inhibitionContact inhibition2. Extracellular matrix2. Extracellular matrix Laminin: Laminin: Epithelia Epithelia FibroblastsFibroblasts Fibronectin : Fibronectin : Epithelia Epithelia FibroblastsFibroblasts3. Growth factors3. Growth factors

Factors influencing regenerationFactors influencing regeneration

GROWTH FACTORSGROWTH FACTORS

EGF, TGF-A, PDGF, aFGF, bFGF, EGF, TGF-A, PDGF, aFGF, bFGF,

IGF-1, IGF-2, VEGF, HGF, MG-CSF, IGF-1, IGF-2, VEGF, HGF, MG-CSF,

M-CSF, G-CSF, ERYTHROPOITIN, M-CSF, G-CSF, ERYTHROPOITIN,

ILs, TNF, IFN, NGF.ILs, TNF, IFN, NGF.

Section BSection BFibrous RepairFibrous Repair

Granulation tissues:Granulation tissues:• Newly formed Newly formed

capillariescapillaries• FibroblastsFibroblasts• Inflammatory cellsInflammatory cells

Granulation tissuesGranulation tissues

• Fibrous repairFibrous repair

• OrganizationOrganization

• Wound healingWound healing

• Fig 4-14

• Fig 4-15

• Healing by first intentionHealing by first intention

• Healing by second intentionHealing by second intention

• Healing under scabHealing under scab

Wound healingWound healing

• Fig 4-18

• Fig 4-19

Systemic factors Systemic factors influencing wound healing:influencing wound healing:

• NutritionNutrition• Metabolic statusMetabolic status• Circulatory statusCirculatory status• HormonesHormones

• Infection Infection • Mechanical factors Mechanical factors • Foreign bodiesForeign bodies• Size, location and types of woundSize, location and types of wound

Local factors Local factors influencing wound healing:influencing wound healing:

Liquefactive necrosisBacterial or fungal infections

Central nervous system

Amebiasis

Fat necrosisTraumatic

Activated pancreatic lipases