Pathophysilogy Chap 1 Cell Pathology · PDF fileAdaptation of Cell Growth and Differentiation ... Physical Agents . ... The cellular response to injurious stimuli depends on (1)

Chapter 1. Cell and mechanisms of cellular dysfunctionsChapter 1. Cell and mechanisms of cellular dysfunctions

General PathophysiologyGeneral Pathophysiology

1Kumar V, Abbas AK, Fausto N, Aster JC, 2010, Robbins and CotranKumar V, Abbas AK, Fausto N, Aster JC, 2010, Robbins and Cotran

Pathologic Basis of Disease 8th Edition, Pathologic Basis of Disease 8th Edition, Saunders Elsevier, Philadelphia, Pennsylvania, USASaunders Elsevier, Philadelphia, Pennsylvania, USA..

Chapter 1. Cell and mechanisms of cellular dysfunctionsChapter 1. Cell and mechanisms of cellular dysfunctions

General PathophysiologyGeneral Pathophysiology

Overview: Cell injury, Cellular Responses to injury , Cell DeathOverview: Cell injury, Cellular Responses to injury , Cell DeathAdaptation of Cell Growth and DifferentiationAdaptation of Cell Growth and Differentiation

HypertrophyHypertrophyHyperplasiaHyperplasiaMetaplasiaMetaplasiaAtrophyAtrophy

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AtrophyAtrophy

Cell Injury and Cell Response to Noxious StimuliCell Injury and Cell Response to Noxious Stimuli

EEtiology of Cell Injurytiology of Cell InjuryStages and Mechanisms of Cell InjuryStages and Mechanisms of Cell InjuryFree Radicals and Cell InjuryFree Radicals and Cell Injury

Mechanisms of Cell DefenseMechanisms of Cell Defense

Nuclear Factor kB (NFkB)Nuclear Factor kB (NFkB)Heat Shock Proteins (HSPs)Heat Shock Proteins (HSPs)

Cellular AgingCellular Aging

Replicative Senescence (Hayflick phenomenon)Replicative Senescence (Hayflick phenomenon)Accumulation of Metabolic and Genetic DamageAccumulation of Metabolic and Genetic Damage

Cell DeathCell Death

ApoptosisApoptosisCauses of ApoptosisCauses of ApoptosisMechanisms and Stages of ApoptosisMechanisms and Stages of Apoptosis

Triggers of ApoptosisTriggers of Apoptosis

Overview: Cell injury, Cellular Responses to injury, Cell DeathOverview: Cell injury, Cellular Responses to injury, Cell Death

Chapter 1.Chapter 1. Cell and mechanisms of cellular dysfunctionsCell and mechanisms of cellular dysfunctions

3 Kumar V, Abbas AK, Fausto N, Aster JC, 2010, Robbi ns and Cotran Pathologic Basis of Disease Kumar V, Abbas AK, Fausto N, Aster JC, 2010, Robbi ns and Cotran Pathologic Basis of Disease 8th Edition, 8th Edition, Saunders Elsevier, Philadelphia, Pennsylvania, USASaunders Elsevier, Philadelphia, Pennsylvania, USA ..

Adaptation of Cell Growth and DifferentiationAdaptation of Cell Growth and Differentiation

HypertrophyHypertrophy anan increase in the size of cells,increase in the size of cells,resulting in anresulting in an increase in the size of the organincrease in the size of the organ ..

HypertrophyHypertrophy

can be can be physiologicphysiologic or or pathologicpathologic


4 Kumar V, Abbas AK, Fausto N, Aster JC, 2010, Robbi ns and Cotran Pathologic Basis of Disease Kumar V, Abbas AK, Fausto N, Aster JC, 2010, Robbi ns and Cotran Pathologic Basis of Disease 8th Edition, 8th Edition, Saunders Elsevier, Philadelphia, Pennsylvania, USASaunders Elsevier, Philadelphia, Pennsylvania, USA ..

physiologicphysiologic or or pathologicpathologic

caused by caused by -- increased increased functional demandfunctional demand-- stimulation by hormones and growth factorsstimulation by hormones and growth factors .


Hyperplasia Hyperplasia -- an increase in the number of cells an increase in the number of cells in an organ or tissue, in an organ or tissue, resultingresulting in increased mass of the organ or tissuein increased mass of the organ or tissue

HyperplasiaHyperplasia

can be can be physiologicphysiologic or or pathologicpathologic


5 http://en.wikipedia.org/wiki/Filehttp://en.wikipedia.org/wiki/File::

Benign_Prostatic_Hyperplasia_nciBenign_Prostatic_Hyperplasia_nci--volvol--71377137--300.jpg300.jpg

caused by caused by -- stimulation by hormones and stimulation by hormones and `̀ growth factorsgrowth factors-- Compensatory hyperplasiaCompensatory hyperplasia .


Metaplasia Metaplasia is ais a reversible change in which one differentiated cell type reversible change in which one differentiated cell type (epithelial or (epithelial or mesenchymal)mesenchymal) is replaced by another cell typeis replaced by another cell type ..

MetaplasiaMetaplasia

columnarcolumnar to to squamoussquamous , (respiratory tract, (respiratory tract ))


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Kumar V, Abbas AK, Fausto N, Aster JC, 2010, Robbi ns Kumar V, Abbas AK, Fausto N, Aster JC, 2010, Robbi ns and Cotran Pathologic Basis of Disease and Cotran Pathologic Basis of Disease 8th Edition, 8th Edition, Saunders Elsevier, Philadelphia, Saunders Elsevier, Philadelphia, Pennsylvania, USAPennsylvania, USA ..

columnarcolumnar to to squamoussquamous , (respiratory tract, (respiratory tract ))

→ → result of a reprogramming of stem cells, or of und ifferentiated mesenchymal result of a reprogramming of stem cells, or of undi fferentiated mesenchymal cells present in connective tissuecells present in connective tissue


Atrophy is reduced size of an organ or tissue resul ting from a decrease in cell size Atrophy is reduced size of an organ or tissue resul ting from a decrease in cell size and numberand number .

AtrophyAtrophy

Atrophy can be physiologic or pathologic. Physiologic atrophy : normal development, the uterus after parturition .


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Physiologic atrophy : normal development, the uterus after parturition .Pathologic atrophy:

Decreased workload (atrophy of disuse) . Loss of innervation (denervation atrophy)Diminished blood supply PressureInadequate nutrition (cachexia ). Malnutrition, chronic inflammatory diseases and can cer (TNF)

Loss of endocrine stimulation

http://www.mayoclinic.org/diseases-conditions/alzheimers-disease/alzheimers-/img-20008229

MechanismMechanism : : .-- ubiquitinubiquitin--proteasome pathwayproteasome pathway-- autophagyautophagy -- autophagic vacuolesautophagic vacuoles → →

residual bodies (lipofuscin)residual bodies (lipofuscin)--


Hypoxia Hypoxia -- ↓↓ of oxygenof oxygen ;Ischemia – ↓ blood irrigation

Etiology of Cell InjuryEtiology of Cell Injury

Reversible injuries Reversible injuries Irreversible injuries Irreversible injuries –– necrosis / apoptosis ?necrosis / apoptosis ?


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Markers of muscular cytolysis: Markers of muscular cytolysis: creatine kinasecreatine kinase and and troponintroponin

http://caribbean.scielo.org/scielo.php?script=sci_arttext&pid=

S0043-31442007000600016&lng=pt&nrm=

Kumar V, et.all, 2010, Kumar V, et.all, 2010, Robbins and Cotran Pathologic Basis of DiseaseRobbins and Cotran Pathologic Basis of Disease


IschemiaIschemia--reperfusion injury reperfusion injury

reperfused tissues may sustain loss of cells in add ition to the cells reperfused tissues may sustain loss of cells in add ition to the cells that are irreversibly damaged at the end of ischemi a.that are irreversibly damaged at the end of ischemi a.


Mechanisms: Mechanisms:


9 Kumar V, et.all, 2010, Kumar V, et.all, 2010, Robbins and Cotran Pathologic Basis of DiseaseRobbins and Cotran Pathologic Basis of Disease

Mechanisms: Mechanisms: ↑↑ ROS ( parenchymal and endothelial cells, leukocytes ) ROS ( parenchymal and endothelial cells, leukocytes )

mitochondrial damage, mitochondrial damage, activation of oxidises in leukocytes, endothelial c ells, or parenchymal cells, activation of oxidises in leukocytes, endothelial c ells, or parenchymal cells, ↓ ↓ cellular antioxidant defense cellular antioxidant defense

Inflammation Inflammation -- ↑↑ cytokines and cytokines and ↑↑ CAMs CAMs →→ recruit circulating neutrophils recruit circulating neutrophils -- ↑↑ complement system complement system –– (( ↑↑ IgM bind complement proteins)IgM bind complement proteins)


Other factors responsible for cell injuries

Physical Agents . Chemical Agents and Drugs.



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Chemical Agents and Drugs.Infectious AgentsImmunologic ReactionsGenetic DerangementsNutritional Imbalances



The cellular response to injurious stimuli depends on (1) the nature of the injury ,

Stages and Mechanisms of Cell InjuryStages and Mechanisms of Cell Injury


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(1) the nature of the injury , (2) its duration, (3) its severity .

The consequences of cell injury depend on (1) the type, (2) state, (3) adaptability of the injured cell .


Cell injury : (1) mitochondria, (2) cell membranes, (3) the machinery of protein synthesis and packagin g,



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(3) the machinery of protein synthesis and packagin g, (5) the DNA in nuclei



Reversible cell injury : cellular swelling / fatty change.. Reversible cell injury : cellular swelling / fatty change.. Irreversible cell injuries Irreversible cell injuries →→ necrosis. necrosis.



13 Kumar V, et.all, 2010, Kumar V, et.all, 2010, Robbins and Cotran Pathologic Basis of DiseaseRobbins and Cotran Pathologic Basis of Disease


Main cellular events involved in cell injuryMain cellular events involved in cell injury



ATP depletion ATP depletion Mitochondrial damageMitochondrial damage . ( . ( ↑↑ Ca2+, ROS, hypoxia, toxins).Ca2+, ROS, hypoxia, toxins).

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Mitochondrial damageMitochondrial damage . ( . ( ↑↑ Ca2+, ROS, hypoxia, toxins).Ca2+, ROS, hypoxia, toxins).→→ mitochondrial permeability transition pore. mitochondrial permeability transition pore. →→ ↓↓ ATP, ATP,

→→ cytochrome cytochrome c c →→ apoptosisapoptosisCalcium influxCalcium influx ..→→ opening of the mitochondrial permeability transitio n pore opening of the mitochondrial permeability transitio n pore → activates → activates phospholipasesphospholipases (membrane damage), (membrane damage),

proteasesproteases (break down membrane and cytoskeletal proteins), (break down membrane and cytoskeletal proteins), endonucleasesendonucleases (DNA and chromatin fragmentation), (DNA and chromatin fragmentation), ATPasesATPases (ATP depletion)(ATP depletion)

Defects in Membrane PermeabilityDefects in Membrane Permeability . ( ATP depletion, calcium. ( ATP depletion, calcium--mediated activation of mediated activation of phospholipases, bacterial toxins, viral proteins, l ytic complement components, phospholipases, bacterial toxins, viral proteins, l ytic complement components, physical and chemical agents via ROS) physical and chemical agents via ROS)

Damage to DNA and Proteins Damage to DNA and Proteins


Free radicals are chemical species that have a sing le Free radicals are chemical species that have a sing le unpaired electron in an outer orbit unpaired electron in an outer orbit

Free Radicals and Cell InjuryFree Radicals and Cell Injury


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Electron structures of common Electron structures of common

reactive oxygen speciesreactive oxygen species

http://www.biotek.com/resources/articleshttp://www.biotek.com/resources/articles

/reactive/reactive--oxygenoxygen--species.htmlspecies.html

Generation of reactive oxygen species

http://www.rndsystems.com/

RadicalsOxidativeStree.aspx


Generation of Free RadicalsGeneration of Free Radicals

ReductionReduction--oxidation reactions (oxidation reactions ( ER, cytosol, mitochondria, peroxisomes, and lysosom es)ER, cytosol, mitochondria, peroxisomes, and lysosom es)

Absorption of radiant energyAbsorption of radiant energy (e.g., ultraviolet light, x(e.g., ultraviolet light, x --rays)rays)



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Absorption of radiant energyAbsorption of radiant energy (e.g., ultraviolet light, x(e.g., ultraviolet light, x --rays)rays)

InflammationInflammation (NADPH oxidase) (NADPH oxidase)

Ischemia, and Ischemia and reperfusion injuriesIschemia, and Ischemia and reperfusion injuries

http://best-skincare.net/rooibos/rooibos-nutrition/

Enzymatic metabolism of exogenous chemicals or Enzymatic metabolism of exogenous chemicals or drugsdrugs

Transition metalsTransition metals such as iron and copper such as iron and copper Fenton Fenton reaction reaction

(H(H22OO22 + Fe+ Fe2+2+➙➙➙➙➙➙➙➙ FeFe3+3+ + OH + OH+ OH + OH--))

Nitric oxideNitric oxide (NO), peroxynitrite anion (ONOO(NO), peroxynitrite anion (ONOO--), ), (endothelial cells, macrophages, neurons)(endothelial cells, macrophages, neurons)


Removal of Free RadicalsRemoval of Free RadicalsEnzymatic mechanismsEnzymatic mechanisms::CatalaseCatalase, , -- peroxisomes, peroxisomes, (2H(2H22OO22➙➙ OO22 + 2H+ 2H22O).O).Superoxide dismutasesSuperoxide dismutases(O(O-- + 2H + 2H ➙➙ HH OO + O+ O ).).



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(O(O--22 + 2H + 2H ➙➙ HH22OO22 + O+ O22).).

Glutathione peroxidaseGlutathione peroxidase(H(H22OO22/2OH+2GSH /2OH+2GSH ➙➙GSSG + 2HGSSG + 2H22O). O). oxidized GS (GSSG) / reduced glutathione oxidized GS (GSSG) / reduced glutathione (GSH) ratio(GSH) ratio →→ oxidative state oxidative state

NonNon--enzymatic mechanismsenzymatic mechanisms::AntioxidantsAntioxidants -- block / inactivate free block / inactivate free radicals. (vitamins E , A, C, various radicals. (vitamins E , A, C, various plant compounds) plant compounds) Molecules that minimize ROS Molecules that minimize ROS formationformation. (transferrin, ferritin, . (transferrin, ferritin, lactoferrin, and ceruloplasmin), lactoferrin, and ceruloplasmin),

Pathologic Effects of Free RadicalsPathologic Effects of Free RadicalsLipid peroxidation in membranesLipid peroxidation in membranesOxidative modification of proteinsOxidative modification of proteins. . Lesions in DNALesions in DNA. .

Kumar V, et.all, 2010, Robbins and Cotran Pathologic Basis of DiseaseKumar V, et.all, 2010, Robbins and Cotran Pathologic Basis of Disease


NFNF--κB (nuclear factor kappaκB (nuclear factor kappa --lightlight --chainchain --enhancer of activated B cells) enhancer of activated B cells)

Nuclear Factor kB (NFkB)Nuclear Factor kB (NFkB)


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NFNF--κB (nuclear factor kappaκB (nuclear factor kappa --lightlight --chainchain --enhancer of activated B cells) enhancer of activated B cells)

-- a protein complex that controls transcription of DNA. a protein complex that controls transcription of DN A. -- cellular responses to stimuli such as stress, cellular responses to stimuli such as stress, cytok inescytokines , , free radicalsfree radicals , , ultraviolet ultraviolet irradiationirradiation , oxidized LDL, and , oxidized LDL, and bacterial or viral bacterial or viral antigensantigens , triggered by protein destruction , triggered by protein destruction . . -- protein responsible for cytokine production and cel l survival. protein responsible for cytokine production and cel l survival. -- five members five members -- p65 (RelA), RelB, cp65 (RelA), RelB, c--Rel, NFRel, NF--κB1 and NFκB1 and NF--κB2. κB2. -- NFNF--κB is regulating cellular responses as inflammatory or immune response, κB is regulating cellular responses as inflammatory or immune response,


Heat shock proteinsHeat shock proteins (HSPs), “(HSPs), “ stress proteinsstress proteins ” “” “ chaperoneschaperones ” ” Induction factors: Induction factors: heat shock (first described), hypoxia, oxidative in jury, glucose heat shock (first described), hypoxia, oxidative in jury, glucose starvation, exposure to heavy metals or antistarvation, exposure to heavy metals or anti--cance r agents cancer agents

Heat Shock Proteins (HSPs)Heat Shock Proteins (HSPs)


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FunctionsFunctions : : control protein biogenesis control protein biogenesis prevent inappropriate stressprevent inappropriate stress--induced protein aggregation induced protein aggregation

ClassificationClassification : : according to m.w. (kDa):according to m.w. (kDa):HSP15HSP15––30, HSP40, HSP60, 30, HSP40, HSP60, HSP70, HSP90 and HSP100. HSP70, HSP90 and HSP100.

http://www.lysosomalstorageresearch.ca/Fabry_RenalClinic/index.phphttp://www.lysosomalstorageresearch.ca/Fabry_RenalClinic/index.php//


Cellular aging is the result of a progressive decli ne in cellular function and viability caused Cellular aging is the result of a progressive decli ne in cellular function and viability caused by genetic abnormalities and the accumulation of ce llular and molecular damageby genetic abnormalities and the accumulation of ce llular and molecular damage . .

Overview Overview


Theories:Theories:

“Our destination is never a place but rather a new way of looking at things.““Our destination is never a place but rather a new way of looking at things.“

Henri MillerHenri Miller

20https://jessbanda.wordpress.com/tag/cellular-aging/

TheThe replicative senescencereplicative senescence

Accumulation of metabolic and genetic damageAccumulation of metabolic and genetic damage . .


Normal cells have a limited Normal cells have a limited

capacity for replicationcapacity for replication

Replicative senescence (Hayflick phenomenon)Replicative senescence (Hayflick phenomenon)


21 http://www.biooncology.com/molecular

-causes-of-cancer/replicative-immortality/ http://pamelamaloney.com/health-products/telomerase-activation/


The amount of oxidative damage, → important cause of senescence. 1) ↑ longevity among different species / ↓ mitochondrial generation of superoxide (2) overexpression of SOD and CAT ↑ life span

Accumulation of metabolic and genetic damageAccumulation of metabolic and genetic damage


22Kumar V, et.all, 2010, Robbins and Cotran Pathologic Basis of DiseaseKumar V, et.all, 2010, Robbins and Cotran Pathologic Basis of Disease


Calorie restrictionCalorie restriction →→ prolonging life spanprolonging life span

mechanism is not fully established,mechanism is not fully established,

-- ↑↑family of proteins called family of proteins called sirtuinssirtuins →→ expression of several genes whose products increase longevity. expression of several genes whose products increase longevity. → → reduce apoptosis, stimulate protein folding, and in hibit the effects of ROS. reduce apoptosis, stimulate protein folding, and in hibit the effects of ROS.

Accumulation of metabolic and genetic damageAccumulation of metabolic and genetic damage


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→ → reduce apoptosis, stimulate protein folding, and in hibit the effects of ROS. reduce apoptosis, stimulate protein folding, and in hibit the effects of ROS. →→ increase insulin sensitivity and glucose metabolism , increase insulin sensitivity and glucose metabolism , ResveratrolResveratrol -- ↑ sirtuins → increase life span.↑ sirtuins → increase life span.

http://www.impactaging.com/papers/v4/n8/full/100481 .htmlhttp://www.impactaging.com/papers/v4/n8/full/100481 .html

--↓ Insulin↓ Insulin--like growth factor 1 (IGFlike growth factor 1 (IGF--1), “somatomedin C1), “somatomedin C ””

-- ↑↑AMPK ( AMP AMPK ( AMP --activated protein kinase)activated protein kinase)


TABLE TABLE ---- Features of Necrosis and Apoptosis Features of Necrosis and Apoptosis

Necrosis / ApoptosisNecrosis / Apoptosis


FeatureFeature NecrosisNecrosis ApoptosisApoptosis

Cell sizeCell size Enlarged (swelling)Enlarged (swelling) Reduced (shrinkage)Reduced (shrinkage)

NucleusNucleus Pyknosis Pyknosis Fragmentation into Fragmentation into

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NucleusNucleus Pyknosis Pyknosis ➙➙➙➙➙➙➙➙karyorrhexis karyorrhexis ➙➙➙➙➙➙➙➙karyolysiskaryolysis

Fragmentation into Fragmentation into nucleosomenucleosome--size fragmentssize fragments

Plasma Plasma membranemembrane

DisruptedDisrupted Intact; altered structure, Intact; altered structure, especially orientation of especially orientation of lipidslipids

Cellular contentsCellular contents Enzymatic Enzymatic digestion; may leak digestion; may leak out of cellout of cell

Intact; may be released in Intact; may be released in apoptotic bodiesapoptotic bodies

Adjacent Adjacent inflammationinflammation

FrequentFrequent NoNo

Physiologic or Physiologic or pathologic rolepathologic role

Invariably Invariably pathologic pathologic (culmination of (culmination of irreversible cell irreversible cell injury)injury)

Often physiologic, means of Often physiologic, means of eliminating unwanted cells; eliminating unwanted cells; may be pathologic after may be pathologic after some forms of cell injury, some forms of cell injury, especially DNA damageespecially DNA damage

Kumar V, et.all, 2010, Robbins and Cotran Pathologic Basis of DiseaseKumar V, et.all, 2010, Robbins and Cotran Pathologic Basis of Disease


Autophagy is a process in which a cell eats its own contents. Nobel Prize - Yoshinori Ohsumi 2016!

AutophagyAutophagy


-- survival mechanism in nutrient survival mechanism in nutrient


-- survival mechanism in nutrient survival mechanism in nutrient deprivationdeprivation

-- in advanced stages, autophagy in advanced stages, autophagy triggers cell death that is triggers cell death that is distinct from necrosis and distinct from necrosis and apoptosis. apoptosis.

-- involved as a mechanism of cell loss involved as a mechanism of cell loss in degenerative diseases of in degenerative diseases of the nervous system and the nervous system and muscle.muscle.


ApoptosisApoptosis or or programmed cell deathprogrammed cell death is a pathway of cell death that is induced by a is a pathway of cell death that is induced by a tightly regulated suicide program in which cells de stined to die activate enzymes that degrade tightly regulated suicide program in which cells de stined to die activate enzymes that degrade the cells' own nuclear DNA and nuclear and cytoplas mic proteins. the cells' own nuclear DNA and nuclear and cytoplas mic proteins.

ApoptosisApoptosis


26 Kumar V, et.all, 2010, Robbins and Cotran Pathologic Basis of DiseaseKumar V, et.all, 2010, Robbins and Cotran Pathologic Basis of Disease


Apoptosis in Physiologic SituationsApoptosis in Physiologic Situations-- Embryogenesis Embryogenesis -- Involution of hormoneInvolution of hormone --dependent tissues upon hormone withdrawal dependent tissues upon hormone withdrawal

Causes ofCauses of ApoptosisApoptosis


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-- Involution of hormoneInvolution of hormone --dependent tissues upon hormone withdrawal dependent tissues upon hormone withdrawal -- Cell loss in proliferating cell populations, Cell loss in proliferating cell populations, -- Elimination of potentially harmful selfElimination of potentially harmful self--reactive l ymphocytes, reactive lymphocytes, -- Death of host cells that have served their useful p urpose, (neutrophils in an acute Death of host cells that have served their useful p urpose, (neutrophils in an acute inflammatory response, and lymphocytes at the end o f an immune response)inflammatory response, and lymphocytes at the end o f an immune response)

Apoptosis in Pathologic ConditionsApoptosis in Pathologic Conditions-- DNA damage. DNA damage. -- Accumulation of misfolded proteins. (ER stress)Accumulation of misfolded proteins. (ER stress)-- Cell death in viral infections, Cell death in viral infections, -- Cell death in tumors and cellular rejection of tr ansplants.Cell death in tumors and cellular rejection of tran splants.


Initiation phaseInitiation phase , , -- some caspases become catalytically activesome caspases become catalytically activethe intrinsic, or mitochondrial, pathwaythe intrinsic, or mitochondrial, pathway , , the extrinsic, or death receptorthe extrinsic, or death receptor––initiated, pathwa yinitiated, pathway

Execution phaseExecution phase , , -- other caspases trigger the degradation of cellular componentsother caspases trigger the degradation of cellular components

Mechanisms and Stages ofMechanisms and Stages of ApoptosisApoptosis


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Execution phaseExecution phase , , -- other caspases trigger the degradation of cellular componentsother caspases trigger the degradation of cellular components


The Extrintrinsic Pathway of ApoptosisThe Extrintrinsic Pathway of Apoptosis



Death receptors - contain death domain(Some TNF receptor family do not contain cytoplasmic death domains; their function is to activate inflammatory cascades).

29 Kumar V, et.all, 2010, Kumar V, et.all, 2010,

Robbins and Cotran Pathologic Basis of DiseaseRobbins and Cotran Pathologic Basis of Disease

domains; their function is to activate inflammatory cascades). type 1 TNF receptor (TNFR1) Fas (CD95),

Fas + Fas ligand (FasL ). → binding site for adapter proteinFADD (Fas-associated death domain)

binds procaspase-8 , (multiple pro-caspase-8 molecules are thus brought into proximity, and they cleave one another to generate active caspase-8 )

inhibited by FLIP,

(binds to pro-caspase-8 but cannot cleave and activate the

caspase because it lacks a protease domain)


The Intrinsic (Mitochondrial) Pathway of ApoptosisThe Intrinsic (Mitochondrial) Pathway of Apoptosis



Deprivation of survival signals, DNA damage, ER stress, → Bim, Bid

↓ anti-apoptotic proteins, - Bcl -2, Bcl-x,


↓ anti-apoptotic proteins, - Bcl -2, Bcl-x, and Mcl-1. ↑proapoptotic effectors, Bax and Bak ,

↑ mitochondrial permeability→ release of pro-apoptotic molecules (death inducers) into the cytoplasm. (cytochrome c )

cytochrome c + Apaf-1 (apoptosis-activating factor-1), → apoptosome

bind procaspase-9 , →caspase-9.


The Execution Phase of ApoptosisThe Execution Phase of Apoptosis



the death receptor pathway initiator caspase-8 mitochondrial pathway initiator caspase-9 ,

executioner caspases, caspase-3 and -6 ,

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- activate DNase → characteristic cleavage of DNA into nucleosome-sized pieces - degrade structural components of the nuclear matrix , - degrade the cytoskeleton

-formation of apoptotic bodies

- phosphatidylserine “flips” out and is expressed on the outer layer of the membrane, where it is recognized by several macrophage receptors


Triggers of ApoptosisTriggers of Apoptosis



Growth Factor Deprivation – ↓ Bcl-2 and Bcl-x and ↑ Bim

DNA Damage (genotoxic stress) - p53. → arrests the cell cycle (at the G1 phase) to allow time for repair. - - / damage is too great - p53 → ↑ Bax, Bak, → triggers apoptosis

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- - / damage is too great - p53 → ↑ Bax, Bak, → triggers apoptosis

Protein Misfolding (ER stress) - unfolded / misfolded proteins → activates caspases → apoptosis.

TNF Receptor Family. Autoimune response (FasL on T cells binds to Fas on the neighboring lymphocytes → elimination of lymphocytes that recognize self-antigens)

Cytotoxic T Lymphocyte (CTLs) –- recognize foreign antigens on the

surface of infected host cells,- secrete perforin ,

→ promotes entry of granzymes .→ activate a variety of cellular caspases 3-6.

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Pathophysilogy Chap 1 Cell Pathology · PDF fileAdaptation of Cell Growth and Differentiation ... Physical Agents . ... The cellular response to injurious stimuli depends on (1)