Robbins Essential Pathology_p011-016.pdf

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1 Cell Injury and Cell Death O U T L I N E Overview of Cell Injury, 1 Oxidative Stress, 7 Causes of Cell Injury, 1 Hypoxia and Ischemia, 8 Reversible Cell Injury, 1 Toxin-Mediated Cell Injury, 9 Cell Death, 2 Endoplasmic Reticulum (ER) Stress, 9 Necrosis, 3 DNA Damage, 9 Apoptosis, 3 Cellular Aging, 9 Other Pathways of Cell Death, 6 Cellular Adaptations to Stress, 11 Mechanisms of Cell Injury and Death, 7 Pathologic Accumulations in Cells, 12 In medeval mes, dseases were arbued o “evl umors, ” “masma, ” bo deprve ssues o oxygen and, n e case o scema, ces are and oer equally nebulous and unprovable causes. One o e mos aso dened essena nurens and oxc meaboes are aowed o undamenal advances n uman bolog y and medcne was e real- bud up zaon a e cell s e srucural and unconal un o lvng organ-    Toxns, wc abound n e envronmen, as we as some terapeu- sms and abnormales n cells underle all dseases: Indvduals are tc drugs sck because er cells are sck. All dseases sare e common eaure    Envronmenta nsuts, suc as pysca rauma, radaon exposure, a ey aler cellular uncon and srucure. ereore, e ounda- and nurona mbaances on o paoog y and medcne s an undersandng o ow ces are    Genetc abnormates, ncudng muaons a mpar e uncon njured, e eme o s rs caper. o varous essena proens and oer muaons a ead o e accumuaon o damaged DNA or abnorma, msoded proens, bo o wc cause ce dea  ey canno be repared or correced OVERVIEW OF CELL INJURY   Immunoogc reactons agans se angens (as n auommune ds- eases) or envronmena angens (as n aerges), wc cause ce In response to stress, cells may adapt, may be injured reversibly njur y, oten by rggerng nlammaon and recover, or may be irreversibly damaged and die.    Agng, a orm o sow, progressve ce njur y Ces normay manan a seady sae, caed omeostass, despe beng consany exposed o couness poenay damagng agens. Ces dea w exerna or nerna sresses by undergong canges a are grouped no ree broad caegores. REVERSIBLE CELL INJURY    Adaptatons are aeraons a enabe ces o cope w sresses w- Reversible injury is characterized by functional and structural ou damage, suc as ncreased musce mass n response o ncreased changes in cells that are not permanent. workoad. e major ceuar adapaons and er pysoogc and e eares canges assocaed w ce njur y mosy afec cyo- paoogc sgncance are summarzed a e end o e caper. pasmc srucures bu do no damage nuce (nucear damage s usuay    Reversbe njury reers o srucura and uncona abnormaes a rreversbe) and ncude e oowng: can be correced  e njurous agen s removed. I e njury s per-    Sweng of ce s as a resu  o n ux o wae r. T  s s usu a  y c aus e d ssen or severe,  can become rreversbe and ead o ce dea. In + by a ure o  e adenos  ne  r po spae ( ATP ) -d ep end e n Na many cases, ces de wou raversng a deecabe reversbe pase. + K p asma membrane pump du e o d e cre as e d ge nera  on o    Ce deat s e end resu o njur y. As we dscuss aer, ere are + ATP or p asma membrane d amage. Te  oss o  n rac e u  ar K wo major paways o ce dea, necross and apoposs, and ey + and comp ens aor y  n  ux o Na br ngs waer w    o man- occur upon exposure o a varey o njurous agens.  an osmo c b a  ance, resu   ng n p asma me mbrane a er a  ons , Causes of Cell Injury ncudng bebbng , oss o m c rov    and swe  ng o m o con - dr  a and  e endop as m c re  c u u m ( E R) (Fg. 1.1). Te so - Diverse insults cause cell injury or death and result in disease. og c canges are sub e, bu organs may app e ar g rossy swo en ese njurous nsus ncude: and p a e (due o compress on o c ap   ar  es ).    Infectous patogens, wc njure ces by producng oxns, ner-    Fatty cange. In organs a are acvey nvoved n meabosm erng w crca ceuar uncons, or by smuang mmune (e.g., ver, ear), oxc njur y dsrups meaboc paways and responses a damage neced ces n e course o r yng o erad- eads o rapd accumuaon o rgycerde-ed pd vacuoes. cae e necon    Eosnopa. e cyopasm o njured ces appears eosnopc    Hypoxa (reduced oxygen suppy) and scema (reduced bood (red n emaoxyn-and-eosn [H&E] sans) because o oss o suppy), wc are caused by bockage o areres or oss o bood; 1 2 CHAPTER 1 Cell Injury and Cell Death NORMAL CELL Reversible Recovery injury Swelling of Condensation endoplasmic of chromatin reticulum and mitochondria Membrane blebs Myelin figure Membrane blebs Progressive injury Breakdown of plasma membrane, Cellular organelles, and fragmentation nucleus; leakage of contents Inflammation APOPTOSIS Apoptotic body Phagocytosis of apoptotic cells Phagocyte and fragments NECROSIS Fig. 1.1 Reversible cell injury, necrosis, and apoptosis. The figure illustrates the sequence of events in cell injury that culminate in necrosis or apoptosis. Myelin figures are collections of phospholipids in concentric layers released from damaged plasma membranes. In cells undergoing necrosis, mitochondria often contain amorphous densities visible by electron microscopy, of unknown significance. RNA, wc bnds e bue emaoxyn san. e eosnopa pospor y  a on and AT P ge ne ra  on ) e ve n a e r res ou  on o  e becomes more pronounced w progresson oward necross. or g na  njur y ; atered str uc ture and f unc ton of te pa sma mem-    “Myen gures” composed o pospopds derved rom damaged brane and ntraceuar me mbranes; and DNA damage and oss of ceuar membranes appear n e cyoso. cromatn str uc tura nteg r t y    e mtocondra may swe.    e ER may become daed, w deacmen o rbosomes and CELL DEATH dssocaon o poysomes, ang proen syness.   Nucear cromatn may cump. Necrosis and apoptosis, the two main forms of cell death, differ in    ese aeraons become more severe  e njur y progresses o e causes, mechanisms, and functional consequences. rreversbe pase o necross, cumnang n oss o pasma mem- Necross and apoposs are usuay dsnc orms o ce dea, w d- brane negry and breakdown o e nuceus. eren morpoogc canges and oer dsngusng eaures (Tabe 1.1). W  p erssen or excessve nox  ous exp osures ,  njure d ce s Necross may be oug o as “accdena” ce dea, relecng severe p ass a nebu ous “p o n o no reur n” and u nd ergo ce  de a . njury a rreparaby damages so many ceuar componens a e ces A  oug   ere are no d e  n  ve mor poog  c or b o cem  c a  cor- smpy “a apar”. Wen ces de by necross, ere s a oca nlamma- re aes o r re versb  y,  s c onssen y carac er  z e d by   re e pe- ory response a cears e scene o e “accden. ” By conras, apopo- nomena:  e nabty to restore mtocondr a f unc ton (oxd a ve ss s “reguaed” ce dea, because  s medaed by dened moecuar  CHAPTER 1 Cell Injury and Cell Death 3 Table 1.1 Features of Necrosis and Apoptosis Feature Necrosis Apoptosis Cell size Enlarged (swelling) Reduced (shrinkage) Nucleus Pyknosis → karyorrhexis → karyolysis Fragmentation into nucleosome-sized fragments Plasma membrane Disrupted Intact; altered structure, especially orientation of lipids Cellular contents Enzymatic digestion; may leak out of cell Intact; may be released in apoptotic bodies Adjacent inflammation Frequent No Physiologic or pathologic role Invariably pathologic (culmination of Often physiologic means of eliminating unwanted irreversible cell injury) cells; may be pathologic after some forms of cell injury, especially DNA and protein damage paways a are acvaed under specc crcumsances and k ces ces are dead (Fg. 1.3). s orm o necross s caracersc w surgca precson, wou nlammaon or e assocaed coaera o ypoxa-nduced ce dea, caused mos commony by a oss damage. In some suaons, ce dea may sow eaures o bo necross o bood suppy (scema). e resuan necross, caed nfarc- and apoposs, or may sar w apoposs and progress o necross, so e ton, s seen n mos sod organs, suc as e ear and kdneys. dsncons may no be as absoue as once oug. Nevereess,  s use-    In quefactve necross, e dead ces are dgesed by reeased u o consder e wo orms as argey nonoverappng paways o ce enzymes (Fg. 1.4). s s seen n necross resung rom bac- dea because er prncpa mecansms and uncona consequences era and unga necons and n scemc narcs o e bran are usuay dferen. (even  sere).    Gangrenous necross s a cnca erm used or e dea o sot s- Necrosis sue and s oten apped o a mb a as os s bood suppy and Necrosis is the result of severe injury and is a pathologic process in as undergone coaguave necross nvovng mupe ssue ayers. which cells spill their contents into the extracellular milieu, caus- I resus rom scema (e.g., rom dabec vascuar dsease, afec- ing local inammation. ng e ower mbs) and s caed dry gangrene  e dead ssue e amarks o necross are: remans nac or wet gangrene  e ssue quees, as s common    Dssouton of ceuar membranes, ncudng e pasma membrane oowng supermposed bacera necon. and ysosoma membranes, because o damage o membrane pds    Caseous necross s caracersc o ubercuoss and some unga and acvy o pospopases necons suc as sopasmoss. e dead ssue breaks down,    Leakage of ysosoma enzymes a dges e ce creang a ceesy conssency on gross examnaon (Fg. 1.5).    L oca nlammaton n response o e reeased conens o dead Mcroscopcay, e necroc ocus s a coecon o ragmened ces. S ome specc componens o ese conens ave been caed or ysed ces w an amorpous granuar pnk (eosnopc) damage-assocaed moecuar paerns (DAMPs). ese reeased appearance. Ceuar ounes canno be dscerned, and ere s acors ncude ATP (rom damaged mocondra), urc acd (a oten a perpera coecon o macropages ormng a granuoma. breakdown produc o DNA), and numerous oer moecues a    Fat necross reers o oca areas o a desrucon, ypcay are normay conaned wn eay ces and wose reease resung rom e reease o acvaed pancreac pases no e ndcaes severe ce njur y. ese moecues are recognzed by subsance o e pancreas and e peronea cavy. s occurs recepors expressed by macropages and mos oer ce ypes, n acue pancreas (Caper 13). Fay acds are reeased and and rgger pagoc yoss o e debrs, as we as e producon combne w cacum o produce grossy vsbe caky we o c yoknes a nduce nlammaon (see Caper 2). Inlamma- areas (a saponcaon), wc enabe e surgeon and e or y ces produce more proeoyc enzymes a exacerbae e paoogs o deny e esons (Suppemena eFg. 1.1). On damage and e subsequen reacon, un e necroc ssue as soogc examnaon, e oc o necross conan sadowy been ceared. ounes o necroc a ces surrounded by basopc cacum deposs and an nlammaor y reacon e man causes o necross ncude scema, exposure o mcro-    Fbrnod necross s a caracersc mcroscopc ndng seen ba oxns, burns and oer orms o cemca and pysca njury, and mos commony n mmune reacons n wc compexes o unusua suaons n wc enzymes eak ou o ces and njure adjacen angens and anbodes and exravasaed pasma proens are ssues (as n pancreas). A ese nang rggers ead o rreparabe deposed n e was o bood vesses, were ey ave a brg damage o numerous ceuar componens, wc cumnae n mem- pnk, amorpous appearance remnscen o brn (Fg. 1.6). brane damage, e bass or e subsequen seps n necross. e aboraory dagnoss o necross may be made by deecng an Morphology. Necroc ces sow more dfuse cyopasmc eosno- ncrease n serum eves o nraceuar proens, wc eak ou o e pa compared w a seen n reversbe njur y (Fg. 1.2). Nuce necroc ces because o membrane damage. s s e bass o measur- undergo sequena canges, rom condensaon o croman (pyk- ng serum roponn or dagnoss o myocarda narcon, ransamnases noss) o ragmenaon o nuce (karyorrexs) o er compee or ver dsease, and pancreac enzymes suc as amyase or pancreas. dssouon (karyoyss). Necross rom dferen causes s manesed by dferen mor- Apoptosis pooges, and recognon o ese paerns s epu or deermn- Apoptosis is a form of cellular suicide that eliminates cells that are ng e underyng eoog y : no longer needed or are damaged beyond repair, without eliciting    In coaguatve necross, e underyng ssue arcecure s a potentially harmful inammatory response. preser ved, a eas or some me, even oug e consuen  CHAPTER 1 Cell Injury and Cell Death 3.e1 Supplemental eFig. 1.1 Fat necrosis. The areas of white chalky deposits represent foci of fat necrosis with calcium soap formation (saponification) at sites of lipid breakdown in the mesentery. (Courtesy of Dr. James Crawford, Department of Pathology, Zucker School of Medi- cine at Hofstra/Northwell.) 4 CHAPTER 1 Cell Injury and Cell Death A B Fig. 1.2 Morphologic changes in reversible and irreversible cell injury (necrosis). (A) Normal kidney tubules with viable epithelial cells. (B) Early (reversible) ischemic injury showing surface blebs, increased eosinophilia of cytoplasm, and swelling of occasional cells. (C) Necrotic (irreversible) injury of epithelial cells, with loss of nuclei and fragmentation of cells and leakage of contents. (Courtesy of Drs. Neal Pinckard and M.A. Ven- katachalam, University of Texas Health Sciences Center, San Antonio.) I N A B Fig. 1.3 Coagulative necrosis. (A) A wedge-shaped kidney infarct (yellow). (B) Microscopic view of the edge of the infarct, with normal kidney (N) and necrotic cells in the infarct (I). The necrotic cells show preserved outlines with loss of nuclei, and an inflammatory infiltrate (dark nuclei interspersed between necrotic tubules) is present. In s paway o ce dea, enzymes acvaed by specc sgnas dsmane e nuceus and cyopasm, generang ragmens a are recognzed and rapdy ceared by pagocyes. Causes of Apoptosis Apoposs occurs n many pysoogc suaons and ser ves o em- nae poenay armu ces and ces a ave ouved er use- uness (Tabe 1.2). I aso occurs as a paoogc even wen ces are damaged, especay wen e damage afecs e ce’s DNA or pro- ens; us, e rreparaby damaged ce s emnaed.    Pysoogc apoptoss    D ea o ces durng e deveopmen o organsms, suc as ces o prmorda ssues a are repaced by maure ssues    D e a  o eu ko c yes ( neu rop s and y mpo c yes ) a er n  ammaor y and  mmune resp ons es ave e m  nae d o endng agens    E mnaon o dysuncona or auoreacve ympocyes or ympocye precursors, parcuary n e bone marrow and e Fig. 1.4 Liquefactive necrosis. An infarct in the brain showing dissolu- ymus tion of the tissue.  CHAPTER 1 Cell Injury and Cell Death 5 Table 1.2 Physiologic and Pathologic Conditions Associated With Apoptosis Condition Mechanism of apoptosis Physiologic During embryogenesis Loss of growth factor signaling (presumed mechanism) Turnover of proliferative tis- Absence of survival signals or acti- sues (e.g., lymphocytes in vation of death-inducing signals bone marrow and thymus) Involution of hormone- Decreased hormone levels lead to dependent tissues (e.g., reduced survival signals endometrium) Decline of leukocyte Loss of survival signals as stimulus numbers at the end of for leukocyte activation is elim- immune and inflammatory inated responses Elimination of potentially Strong recognition of self antigens harmful self-reactive induces apoptosis by both the Fig. 1.5 Caseous necrosis. Tuberculosis of the lung, with a large area of lymphocytes mitochondrial and death receptor caseous necrosis containing yellow-white (cheesy) debris. pathways Pathologic DNA damage Activation of proapoptotic proteins Accumulation of misfolded Activation of proapoptotic proteins, proteins possibly direct activation of caspases Infections, especially certain Activation of the mitochondrial viral infections pathway by viral proteins Killing of infected cells by cytotoxic T lymphocytes, which activate caspases proens ater asparc acd resdues. e end resu o apopoc ce dea s e cearance o apopoc bodes by pagocyes.   e mtocondra (ntrnsc) patway seems o be responsbe or apoposs n mos pysoogc and paoogc suaons. Moecuar sensors n e cyopasm deec e ack o sur vva sgnas, DNA Fig. 1.6 Fibrinoid necrosis in an artery in a patient with polyarteritis damage, or e accumuaon o msoded proens. ese acvaed nodosa. The wall of the artery shows a circumferential bright pink area sensors nduce e dmerzaon o wo proens (caed BAX and of necrosis with protein deposition and inflammation. BAK) a nser no e mocondra membrane and orm can- nes, eadng o ncreased mocondra permeaby. e cannes aow proapopoc acors (.e., cyocrome c and oer proens) o    Ce oss a aernaes w ce proeraon n ormone-respon- eak no e cyoso, were ey acvae e enzyme caspase-9. A sve ssues suc as e endomerum cascade o addona caspases s acvaed, cumnang n e enzy-    Emnaon o ympocyes a recognze se angens mac breakdown o nuce and cyopasmc srucures. Fragmens    Patoogc apoptoss o nuce and oer organees suc as mocondra are exruded    S evere DNA damage, ater exposure o radaon or cyooxc drugs no ragmens (caed apopoc bodes) a are subsequeny    Accumuaon o msoded proens, gvng rse o ER sress pagocyosed. Because ceuar membranes reman nac, enzymes    C eran necous agens, parcuary some vruses suc as and oer ce conens do no eak ou (as ey do n necross), and epas B and C, wc rgger mmune responses a desroy ere s no nlammaon. e dmerzaon o e efecor moecues neced ces. BAX and BAK s normay prevened by anapopoc moecues o e BCL amy, noaby BCL-2 and B CL-x. ese are acvaed Mechanisms of Apoptosis by grow acors, wc s one way a grow acors promoe There are two pathways of apoptosis, the mitochondrial (or intrin- ce sur vva and subsequen proeraon. Consuve acvaon sic) pathway and the death receptor (or extrinsic) pathway, which o BCL-2 by genec aberraons s seen n umors; n ac, BCL-2 differ in their initiation and molecular signals (Fig. 1.7). sands or B ce ympoma-2, so named or e umor n wc  e bocemca paways o apoposs conro e baance o was dscovered as an oncogene (see Caper 5). dea- and sur vva-nducng sgnas and umaey e acvaon o    e deat receptor (extrnsc) patway of apoptoss. Dea recepors enzymes caed caspases. Caspases are cysene proeases a ceave are pasma membrane recepors o e umor necross acor (TNF)