Robbins Essential Pathology PDF
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Summary
This chapter from Robbins Essential Pathology describes the mechanisms of cell injury and cell death, particularly apoptosis. It details the two main pathways—the mitochondrial (intrinsic) and receptor (extrinsic) pathways, outlining the molecular events involved in each. The importance of caspases and other mediators in triggering apoptosis and the different cell clearance mechanisms are covered.
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6 CHAPTER 1 Cell Injury and Cell Death MITOCHONDRIAL (INTRINSIC) DEATH RECEPT...
6 CHAPTER 1 Cell Injury and Cell Death MITOCHONDRIAL (INTRINSIC) DEATH RECEPTOR (EXTRINSIC) PATHWAY PATHWAY Receptor-ligand interactions FAS TNF receptor Cell injury Mitochondria Growth factor Adaptor proteins withdrawal DNA damage Phagocyte (by radiation, Cytochrome c BCL-2 family toxins, free and other Caspase effectors (BAX, BAK) radicals) proapoptotic activation Protein proteins misfolding Regulators (ER stress) BH3 (BCL-2, BCL-x ) L sensors Endonuclease Breakdown of activation cytoskeleton Nuclear fragmentation Ligands for phagocytic cell receptors Apoptotic body Fig. 1.7 Mechanisms of apoptosis. The two pathways of apoptosis differ in their induction and regulation, and both culminate in the activation of caspases. In the mitochondrial pathway, BH3-only proteins, which are related to members of the BCL-2 family, sense a lack of survival signals or DNA or protein damage. These BH3-only proteins activate effector molecules that increase mitochondrial permeability. In concert with a defi- ciency of BCL-2 and other proteins that maintain mitochondrial permeability, the mitochondria become leaky and various substances, such as cytochrome c, enter the cytosol and activate caspases. Activated caspases induce the changes that culminate in cell death and fragmentation. In the death receptor pathway, signals from plasma membrane receptors lead to the assembly of adaptor proteins into a “death-inducing signaling complex,” which activates caspases, and the end result is the same. ER, Endoplasmic reticulum; TNF, tumor necrosis factor. recepor amy ound on many ces. ese recepors ave a con- ces are removed so qucky and eiceny a ey are oten no den- ser ved cyopasmc “dea doman” a medaes neracon w ed n soogc specmens, even n ssues n wc many ces are oer proens nvoved n ce dea. e prooypc dea recepors dyng by apoposs. are e ype I TNF recepor and FAS (CD95). FAS gand (FASL) s Other Pathways of Cell Death a membrane proen expressed many on acvaed T ympocyes. Wen ese T ces recognze FAS-expressng arges, FAS moe- Aoug necross and apoposs are e bes-dened paways o ce cues are cross-nked by FASL and bnd adapor proens va e dea, severa oer mecansms ave aso been descrbed receny. dea doman. ese en recru and acvae caspase-8, wc, n er mporance n uman dseases remans a opc o nvesgaon, urn, acvaes downsream caspases. e dea recepor paway s bu sudens soud be aware o er names and unque eaures. nvoved n e emnaon o se-reacve ympocyes and n e Necroptoss s nduced by acvaon o specc knases n response kng o arge ces by some cyooxc T ympocyes a express o e cyokne umor necross acor (TNF), wc s produced as FASL par o e os response o mcrobes and oer rrans. Sgnas Cearance of apoptotc fragments. Wen ces undergo apoposs, rom ese knases ead o pasma membrane njur y, as n necross, ey begn o express a number o moecues a are recognzed bu e process s reguaed by specc moecues, ke apoposs, so by recepors on pagocyes. Pagocyes nges and desroy e s consdered o ave eaures o bo. ragmens o apopoc ces, oten wn mnues, beore e ces P yroptoss s a orm o ce dea nduced by bacera oxns n undergo membrane damage and reease er conens. e pago- wc e dyng ce reeases cyoknes, suc as nereukn-1, a cyoss o apopoc ces s so eicen a dead ces dsappear nduce oca nlammaon and ever (ence pyro n e name). wou eavng a race, and nlammaon s vruay absen. Autopagy s a orm o “se-eang” (Greek, paga = o ea) n wc e morpoogc appearance o apopoc ces s dsncve and ces sar ved o nurens dges er own organees and recyce e dferen rom necross. In H&E-saned secons, e nuce appear maera o provde energy or sur vva. In s process, organees pyknoc, because o e condensaon o croman, and e ces are and porons o e cyoso are encosed wn vacuoes, wc srunken, appearng o e n vacuoes (Fg. 1.8). However, apopoc use w ysosomes, and e conens are desroyed by ysosoma CHAPTER 1 Cell Injury and Cell Death 7 aer) and decreased ATP producon. Mocondra aso sequeser moecues, suc as cyocrome c, wose reease no e cyoso s an ndcaor o damage and, as descrbed earer, a rgger or apoposs. C euar membranes are composed o pds and conan proen and carboydrae moecues. ey manan e srucure o ces and organees and ser ve numerous crca ranspor uncons suc as lud and on omeosass. Damage o ysosoma mem- branes, by ROS or oer agens, eads o reease o enzymes a dges e njured ce, e amark o necross. Damage o e pasma membrane resus n oss o ceuar consuens, e end resu o necross. Nuce sore mos o e ce’s genec maera. Nucear damage dsrups ranscrpon-dependen ceuar uncons (.e., proen syness), as we as ce proeraon. Irreparabe damage o DNA rggers apoposs. Oter ceuar components a sufer damage upon exposure o var- ous njurous agens ncude e ER (one se o proen syness and pos-ransaon processng) and e cyoskeeon (e sruc- ura scafod and “moor” o ces). In addon o ce njur y resung rom mparmen o ese nrn- sc srucures, ces may be damaged rom e ousde, or exampe, by e producs o eukocyes durng nlammaor y reacons. Oxidative Stress Oxidative stress refers to cellular abnormalities that are induced by ROS, which belong to a group of molecules called free radicals. Fig. 1.8 Morphologic appearance of apoptotic cells. Apoptotic cells Free radcas are gy reacve moecues w an unpared eec- (some indicated by arrows) in a crypt in the colonic epithelium are shown. (The preparative regimen for colonoscopy frequently induces ron n an ouer orb. ey reac w a norganc and organc mo- apoptosis in epithelial cells, which explains the abundance of dead ecues (e.g., proens, pds, and nucec acds) and remove eecrons cells in this normal tissue.) Note the fragmented nuclei with condensed rom oer moecues, converng em no ree radcas. Boogcay chromatin and the shrunken cell bodies, some with pieces falling off of mporan ree radcas ncude ROS and nrc oxde (Fg. 1.10). them. (Courtesy of Dr. Sanjay Kakar, Department of Pathology, Univer- ROS are produced normay n sma amounts n a ces durng te sity of California San Francisco.) reducton–oxdaton (redox) reactons a occur durng mocon- dra respraon and energ y generaon. In s process, moecuar oxygen s reduced n mocondra o generae waer by e sequen- enzymes. I e process connues because e nuren decency s a addon o our eecrons. s reacon s mperec, owever, no correced, can rgger apoposs by e mocondra paway. and sma amouns o gy reacve bu sor-ved oxc nerme- daes are generaed wen oxygen s ony paray reduced. ese MECHANISMS OF CELL INJURY AND DEATH nermedaes ncude superoxde O , wc s convered o ydro- 2 gen peroxde (H O ) sponaneousy and by e acon o e enzyme The degree of injury from any injurious stimulus varies depending 2 2 superoxde dsmuase. H O s more sabe an O and can cross on the type of the offending agent, its severity, and its duration, as 2 2 2 2+ boogc membranes. In e presence o meas, suc as Fe , H O well as the adaptive ability and genetic makeup of the target cell. 2 2 s convered o e gy reacve ydroxy radca by e Fenon Sma amouns o a oxn or bre perods o scema may cause reacon. e generaon o ree radcas s ncreased by exposure o reversbe njury bu arger doses o e oxn or more proonged scema UV g, radaon and oxns, and durng norma ceuar agng, a may cause necross. Sraed musce n e eg survves scema or 2 o o wc may mpar mocondra uncons. Oxygen deprvaon 3 ours, wereas cardac musce, w s ger meaboc needs, des aso eads o ROS producon because o ncompee reducon o ater 20 o 30 mnues o scema. e genec makeup o e ndvdua oxygen. may aso deermne e reacon o njurous agens. Poymorpsms n genes encodng members o e cyocrome P450 amy afec e ROS are produced n pagocytc eukocytes, many neutrops and macropages, o desroy ngesed mcrobes and oer subsances rae o meabosm o many cemcas and ence e efecs o oxns. durng nlammaon. In e “respraor y” or “oxdave” burs, o- One o e goas o precson medcne s o use genecs o predc ow owng ngeson o a mcrobe, a pagosome membrane enzyme ndvduas w reac o dferen ypes o njurous smu. caayzes e generaon o O , wc s convered o H O. H O s 2 2 2 2 2 Cell injury results from abnormalities in one or more essential n urn convered o a gy reacve compound, ypocore (e cellular components, mainly mitochondria, membranes, and the major componen o ouseod beac), by e enzyme myeoper- nucleus (Fig. 1.9). oxdase, wc s presen n eukocye granues. s s one reason e consequences o mparmen o eac o ese ceuar organees wy nlammaon nended o k necous paogens s oten are dsnc bu overappng. assocaed w njur y o norma ssues. Mtocondra are e ses were ATP, e prmary carrer o energy n Ntrc oxde s anoer reacve ree radca produced n macro- ces, s produced by oxdave posporyaon. Injury due o ypoxa, pages and oer eukocyes durng nlammaor y reacons. I can scema, radaon, or oer nsus mpars oxdave posporya- combne w O o orm a gy reacve compound, peroxyn- 2 on, eadng o e ormaon o reacve oxygen speces (ROS) (see re, wc aso parcpaes n ce njur y. 8 CHAPTER 1 Cell Injury and Cell Death Hypoxia/ischemia Radiation Radiation ROS Mutations Other injurious agents Other injurious agents MITOCHONDRIA CELLULAR MEMBRANES NUCLEUS ATP ROS Damage to lysosomal Damage to plasma membranes membrane Energy- Damage to DNA damage dependent lipids, proteins, Leakage of Impaired transport functions functions nucleic acids enzymes Leakage of cellular contents Reduced Activation protein of caspases Cell injury synthesis NECROSIS NECROSIS APOPTOSIS Fig. 1.9 Principal cellular targets of injurious stimuli. Most injurious stimuli affect mitochondria, cellular mem- branes, or nuclear DNA. Injury to these structures may progress to necrosis or apoptosis. ATP, Adenosine triphosphate; ROS, reactive oxygen species. ROS can damage pds (by peroxdaon), proens (many by Hypoxa (reduced avaaby o oxygen) s seen n suaons o cross-nkng), and DNA (by creang breaks a deoxyymdne res- bood oss, anema, and carbon monoxde posonng (wc ner- dues), and us afec a ceuar componens. er accumuaon eres w e oxygen-carr yng capacy o emogobn). Iscema, or s conroed by enzymes suc as guaone peroxdase and caa- reduced bood low, may be a consequence o arera obsrucon (as ase, wc break down ydrogen peroxde. Increased generaon o n coronar y arer y dsease, e major cause o myocarda narcon, ree radcas durng paoogc njur y over wems ese scavengng or cerebra arer y dsease, e major cause o sroke) or a severe drop mecansms. n bood pressure (sock). ese are some o e mos requen and serous probems n cnca medcne. Hypoxia and Ischemia ATP s produced n mocondra n an eecrocemca reacon Oxygen deciency leads to reduced generation of ATP and failure a depends on e reducon o oxygen (oxdave pospor yaon) of energy-dependent cellular systems (Fig. 1.11). and s g-energ y pospae s requred or membrane ranspor, syness o proens and pds, and urnover o pospopds. I s esmaed a e ces o a eay ndvdua burn 50 o 75 kg o ATP Ischemia ever y day. ereore, oxygen deprvaon and e resung depeon o ATP damages many ceuar componens, as oows: + + Reduced acvy o e pasma membrane ATP-dependen Na -K + pump resus n e nlux o Na and waer, as dscussed earer, eadng o ce sweng and daon o e ER, wc are some o e eares manesaons o ce njur y (see Fg. 1.1). Mitochondrion Anaerobc gycoyss ncreases n an aemp o generae ATP n e absence o oxygen, resung n ncreased producon o acc acd, decreased nraceuar pH, and, consequeny, reduced acvy o Oxidative phosphorylation many nraceuar enzymes. Rbosomes deac rom e ER, eadng o reduced proen syness. ATP Hypoxa may ncrease e generaon o ROS, wc ave many damagng efecs. + Na pump Anaerobic glycolysis Detachment Umaey, ysosoma and mocondra membranes are damaged, of ribosomes ysosoma acd ydroases are acvaed by ow pH, and e ce 2+ begns o dges se, cumnang n necross. Influx of Ca + H O, and Na Glycogen Lactic pH Protein 2 acid synthesis Ischemia–Reperfusion Injury + Efflux of K Restoration of blood ow to an ischemic tissue sometimes para doxically exacerbates tissue injury. ER swelling Cellular swelling e ce njur y a may oow reperuson s key due o ncreased Loss of microvilli producon o ROS by njured ces w damaged mocondra and Blebs by eukocyes, wc are recrued o ge rd o e necroc ces. Fig. 1.10 The functional and morphologic consequences of hypoxia and ese nlammaor y ces may reease enzymes a cause ye more s- ischemia. ATP, Adenosine triphosphate. ER, endoplasmic reticulum. sue damage (see Caper 2). Compemen proens, wc ener e CHAPTER 1 Cell Injury and Cell Death 9 Pathologic effects Radiation Toxins Production of ROS: Lipid peroxidation Membrane damage Reperfusion H O O 2 2 OH 2 Protein Breakdown, Superoxide Hydrogen Hydroxyl modifications misfolding peroxide radical DNA damage Mutations Conversion Decomposition to to H O H O by glutathione 2 2 2 by SOD peroxidase, catalase Removal of free radicals Fig. 1.11 The generation, removal, and role of reactive oxygen species (ROS) in cell injury. The production of ROS is increased by many injurious stimuli. These free radicals are removed by spontaneous decay and by specialized enzymatic systems. Excessive production or inadequate removal leads to accumulation of free radicals in cells, which may damage lipids (by peroxidation), proteins, and DNA, resulting in cell injury. SOD, superoxide dismutase. reperused ssue, may aso conrbue o e njur y, as n oer nlam- sae; and ceran neopasms o proen-secreng ces, parcuary maor y reacons. pasma ce neopasms suc as mupe myeoma. Proen msodng s oug o be e undamena ceuar abnormay n severa neu- Toxin-Mediated Cell Injury rodegenerave dseases (see Caper 17). Deprvaon o gucose and oxygen, as n scema and ypoxa, aso may ncrease e burden o Many environmental and microbial toxins damage cellular com- msoded proens. Dseases caused by msoded proens are sed ponents directly or after conversion to reactive metabolites, often n Tabe 1.3 by cytochrome P450 in liver cells. A cassc, now many sorca, exampe o oxn-medaed ce DNA Damage njury s ver damage oowng naaon o carbon eracorde, a DNA damage that is too great to be corrected by DNA repair cemca once used n e dry ceanng ndusry bu now banned. s mechanisms leads to apoptosis. moecue s convered n e ver no a ree radca a s e cause o Damage o nucear DNA occurs upon exposure o radaon, cemo- ce njury, many by membrane pospopd peroxdaon. Damage erapeuc (ancancer) drugs, and ROS and as a resu o muaons. o e ER membrane causes a decne n e syness o enzymes and Damaged DNA acvaes p53, wc arress ces n e G1 pase o e pasma proens, as we as apoproens, wc are ranspor proens a ce cyce o aow e damage o be repared and aso acvaes DNA orm compexes w rgycerdes, acang rgycerde secreon; s repar mecansms. I ese mecansms a o correc e DNA dam- deec resus n e accumuaon o pds n epaocyes and oer ces age, p53 rggers apoposs by e mocondra paway. us, e ce (seaoss; see aer). e anagesc aceamnopen as a smar mec- “cooses” o de raer an survve w abnorma DNA a as e ansm o acon. I s meabozed o a ree radca by cyocrome P450 poena o nduce magnan ransormaon o e ce. Predcaby, enzymes, and acue overdose o s drug s e mos requen cause o muaons n p53 a nerere w s aby o arres ce cycng or o serous ver damage n e Uned Saes and oer deveoped counres. nduce apoposs are assocaed w numerous cancers (see Caper 5). Endoplasmic Reticulum (ER) Stress Cellular Aging The accumulation of misfolded proteins in the ER can stress adap- Cells age because of accumulation of mutations, progressively tive mechanisms and trigger apoptosis. decreased replication, and defective protein homeostasis. Wen mpropery oded proens accumuae n e ER, ey rs Peope age because er ces age. Aoug muc o e pubc’s acvae a proecve reacon caed e unfoded proten response, n aenon on agng s ocused on s cosmec and pysca conse- wc proen ransaon s reduced and e producon o caperones quences, e greaes danger o ceuar agng s a promoes e (moecues a manan newy syneszed proens n er proper deveopmen o many degenerave, meaboc, and neopasc dsor- sape) s ncreased (Fg. 1.12). I e oad o msoded proens s oo ders. Numerous nrnsc moecuar abnormaes are beeved o cause grea, e ce des by e mocondra paway o apoposs; n s e agng o ces (Fg. 1.13). way, ces a can no onger uncon are emnaed. Accumuaon o mutatons n DNA, wc occurs nauray and Inraceuar accumuaon o msoded proens may be caused may be enanced by ROS and envronmena muagens. by abnormaes a ncrease e producon o msoded proens D ecreased repcaton of ces because o progressve oss o e or reduce e aby o emnae em. ese may resu rom gene enzyme eomerase, wc manans e norma eng o e muaons, suc as ose responsbe or c ysc bross, a ead o enzyme eomeres. ese sor DNA sequences a e ends o cro- e producon o proens a canno od propery : agng, wc s mosomes proec e ends rom uson and degradaon. Teomeres assocaed w a decreased capacy o correc msodng; necons, soren w ever y repcaon bu can be mananed by e acvy especay vra necons, wen arge amouns o mcroba proens o e enzyme eomerase. Because mos ces (excep germ ces) are syneszed wn ces, exceedng e ce’s proen-odng conan e or no eomerase, eomere sorenng s nevabe capacy ; ncreased demand or secreor y proens suc as nsun n dvdng ces. W compee oss o eomeres durng ceuar n nsun-ressan saes; canges n e nraceuar pH and redox 10 CHAPTER 1 Cell Injury and Cell Death Mild ER Stress Severe ER Stress Misfolded proteins ER lumen ER membrane P P P P P P P P P P Sensor of misfolded proteins Signaling Signaling Cytosol Increased Reduced Increased Activation of Activation of synthesis of protein protein BH3 proteins caspases chaperones synthesis degradation Reduced load of misfolded proteins ADAPTIVE TERMINAL UNFOLDED PROTEIN UNFOLDED PROTEIN RESPONSE RESPONSE: APOPTOSIS Fig. 1.12 The unfolded protein response and endoplasmic reticulum (er) stress. The presence of misfolded proteins in the ER is detected by sensors in the ER membrane (BH3-only proteins, mentioned earlier) that trigger an adaptive unfolded protein response, which can protect the cell from the harmful consequences of the misfolded proteins. When the amount of misfolded proteins is too great to be corrected, the mitochon- drial pathway of apoptosis is induced and the irreparably damaged cell dies; this is also called the terminal unfolded protein response. Table 1.3 Diseases Caused by Misfolded Proteins Disease Affected protein Pathogenesis Diseases Caused by Mutant Proteins That are Degraded, Leading to Their Deficiency Cystic fibrosis CFTR Loss of CFTR leads to defects in chloride transport Familial hypercholesterolemia LDL receptor Loss of LDL receptor leads to hypercholesterolemia Tay-Sachs disease Hexosaminidase α subunit Lack of the lysosomal enzyme leads to storage of GM ganglio- 2 sides in neurons Diseases Caused by Misfolded Proteins That Result in ER Stress–Induced Cell Loss Retinitis pigmentosa Rhodopsin Abnormal folding of rhodopsin causes photoreceptor loss and cell death, resulting in blindness sc Creutzfeldt-Jakob disease Prions Abnormal folding and aggregation of PrP causes neuronal cell death Alzheimer disease Aβ peptide Abnormal folding of Aβ peptide causes aggregation within neu- rons and apoptosis Diseases Caused by Misfolded Proteins That Result From Both ER Stress–Induced Cell Loss and Functional Deficiency of the Protein Alpha-1-antitrypsin deficiency α-1 antitrypsin Storage of nonfunctional protein in hepatocytes causes apoptosis; absence of enzymatic activity in lungs causes destruction of elastic tissue, giving rise to emphysema Selected illustrative examples of diseases are shown in which protein misfolding is thought to be the major mechanism of functional derangement or cell or tissue injury. CFTR, Cystic fibrosis transmembrane conductance regulator; LDL, low-density lipoprotein. CHAPTER 1 Cell Injury and Cell Death 11 Environmental and Telomere Abnormal Calorie metabolic insults shortening protein homeostasis restriction ROS? Insulin/IGF signaling TOR Accumulation of Cellular Proteins, mutations in DNA replication misfolded proteins Defective Altered DNA repair transcription DECREASED DECREASED CELL FUNCTIONS, CELL LOSS CELL FUNCTIONS CELL LOSS DNA repair CELLULAR AGING Protein homeostasis COUNTERACTS AGING Fig. 1.13 Mechanisms of cellular aging. DNA damage, replicative senescence, and decreased and misfolded proteins are among the best-described mechanisms of cellular aging. Some environmental stresses, such as calorie restriction, counteract aging by activating various signaling pathways and transcription factors. IGF, Insulin-like growth factor; ROS, reactive oxygen species; TOR, target of rapamycin. agng, e “naked” cromosome ends acvae e DNA damage organ njury e sress s no reeved. For exampe, cardac yper- response, causng e ces o ener a sae o repcave senescence. ropy can cause myocarda scema due o reave ack o oxygen D efectve proten omeostass, due o ncreased urnover and devery, and evenuay gve rse o cardac aure. decreased syness o nraceuar proens, ogeer w accu- Hyperpasa s an ncrease n e number o ces n an organ a sems muaon o msoded proens. rom ncreased proeraon, eer o ess-dferenaed progenor Atered sgnang patways a may afec responses o grow ac- ces or, n some nsances, dferenaed ces. Hyperpasa occurs ors. ere as been grea neres n denng ese paways, n e ssue conans ce popuaons capabe o repcaon and may par because o e nrgung obser vaon a caore resrcon occur concurreny w yperropy and oten n response o e proongs e. One possby s a caore resrcon reduces sg- same smu. Hyperpasa can be pysoogc or paoogc and, n nang by nsun-ke grow acor, so ces cyce ess and sufer bo suaons, ceuar proeraon s smuaed by ormones and ewer DNA repcaon–reaed errors. grow acors a are produced by a varey o ce ypes. Posparum In addon o ese nrnsc abnormaes, damaged and dyng enargemen o e breas due o ncreased proeraon o ducuar ces nduce ow-eve nlammaton, and cronc nlammaon pre- epeum s an exampe o pysoogc yperpasa nduced by or- dsposes o many dseases, suc as aerosceross, ype 2 dabees, mones. Grow acors are responsbe or smuang proeraon o and some ypes o cancer. survvng ces ater dea or remova o some o e ces n an organ (e.g., grow o resdua ver oowng para epaecomy, caed com- pensatory yperpasa). Paoogc yperpasa s ypcay e resu o CELLULAR ADAPTATIONS TO STRESS napproprae and excessve smuaon by ormones and grow ac- Adaptations are reversible changes in the number, size, phenotype, ors, as n endomera yperpasa resung rom a dsurbed esrogen– metabolic activity, or functions of cells in response to changes in progeserone baance. Bengn prosac yperpasa s nduced by their environment. androgens and can cause obsrucon o e low o urne and preds- Ceuar adapaons may be par o pysoogc ceuar responses or pose o urnary rac necons. I s mporan o dsngus yperpa- may be paoogc. Pysoogc adaptatons usuay represen responses sa rom neopasa: Unke neopasc grows, yperpasa s reversbe o ces o norma smuaon by ormones or endogenous cemca wen e grow sgnas abae. In some cases, perssen paoogc medaors (e.g., e ormone-nduced enargemen o e breas and yperpasa, suc as a afecng e endomerum, ses e sage or uerus durng pregnancy), or o e demands o mecanca sress (n e deveopmen o cancer because proerang ces are suscepbe o e case o bones and musces). Patoogc adaptatons are responses o muaons and oncogenc ransormaon. sress a aow ces o moduae er srucure and uncon and us Atropy s a decrease n e number o ces and, ence, may cause an escape njur y, bu a e expense o norma uncon. Pysoogc and organ o srnk. I s caused
