大鼠缺血性急性肾损伤对肝细胞形态学的影响

目的 观察大鼠缺血性急性肾损伤对其肝细胞形态学的影响. 方法 健康SD大鼠30只被分为假手术组( sham)、缺血性急性肾损伤组(IAKI)和双肾切除组(BNx),每组10只.成功制造IAKI模型后24 h经颈总动脉取血进行肾功能和肝功能检测;采用光学显微镜、电子显微镜技术观察缺血性急性肾损伤大鼠的肝脏形态学变化;分别采用免疫组织化学和免疫印迹方法检测IAKI大鼠肝脏多聚二磷酸腺苷核糖聚合酶-1( PARP-1)和Caspase-3蛋白的表达情况. 结果 缺血性急性肾损伤的动物发生了急性肝损伤,肝功能受损.肝脏出现了大小不等坏死病灶.肝细胞损伤的形态学分类包括苍白样坏死、空泡样坏死,固缩性死亡以及细胞凋亡,其中细胞坏死多见.免疫印迹和免疫组织化学染色结果显示,IAKI诱导的肝细胞受损过程中PARP-1和Caspase-3被激活.结论 缺血性急性肾损伤可引起肝细胞坏死和凋亡,但以细胞坏死为主.PARP-1介导细胞死亡、Caspase依赖细胞死亡均参与了IAKI诱导的肝细胞损伤.     

大鼠缺血性肾损伤的细胞聚合糖性死亡与外源性凋亡

目的探讨大鼠肾缺血再灌注所致急性肾损伤时细胞聚合糖性死亡与外源性凋亡。方法应用免疫印迹技术、免疫组织化学染色技术以及光学和电子显微镜技术对缺血60min再灌注24h的大鼠肾组织进行观察和分析。结果免疫印迹分析结果表明,与sham组比较肾缺血再灌注后(AKI组)肾组织PARP-1、caspase-3和TNFRα表达增强。PARP-1、caspase-3免疫组化染色阳性细胞出现在缺血再灌注损伤肾组织,主要分布于肾小管,皮质和髓质外带的肾小管出现了大面积细胞坏死,表现为细胞肿胀,空泡形成,崩解脱落。在髓质外带肾小管坏死细胞之间存在着较多的凋亡细胞,细胞皱缩,核固缩。电镜下坏死细胞肿胀,细胞器也肿胀,崩解消失。凋亡细胞皱缩,界限清楚,核染色质固缩边聚。结论大鼠肾缺血60 min再灌注24 h部分肾小管上皮细胞发生聚合糖性死亡和外源性凋亡。     

红景天苷对急性心肌缺血大鼠心肌细胞凋亡的作用及机制研究

目的：观察红景天苷对急性心肌缺血大鼠心肌细胞凋亡的影响,探讨其可能的分子机制。方法：制备Sprague Dawley大鼠急性心肌缺血模型,随机分为红景天苷高、低剂量组(40 mg/kg、10 mg/kg)、急性心肌缺血组和对照组。原位末端转移酶标记染色法检测心肌组织凋亡情况,免疫印迹法检测心肌组织Bcl-2、Bax、Cytochrome c (Cyt-c)、cleaved caspase-3以及cleaved caspase-9蛋白的表达水平。结果：原位末端转移酶标记染色法显示红景天苷浓度依赖性抑制急性心肌缺血所引起心肌细胞的凋亡;免疫印迹法结果显示,与急性心肌缺血组相比,红景天苷干预后心肌组织中Bcl-2的蛋白表达显著增加,Bax的蛋白表达显著减少,胞浆(cyto)中Cyt-c的蛋白表达水平显著下降,cleaved caspase-3和cleaved caspase-9表达均显著降低。结论：红景天苷具有抗心肌细胞凋亡的作用,其作用机制可能是通过抑制线粒体通路减少细胞的凋亡。本实验为红景天苷可作为临床上治疗缺血性心脏病提供实验依据。     

P53在急性肾损伤小鼠肾脏的表达及其与细胞凋亡的关系

 目的：探讨缺血再灌注致急性肾损伤（AKI）小鼠肾脏不同部位P53的表达及其与细胞凋亡的关系。方法：采用随机对照动物实验方法,将18只小鼠随机分为假手术组、AKI组及P53抑制剂pifithrin-alpha（PFT-α）组,每组6只。采用双侧肾蒂夹闭45 min后松开动脉夹的方法建立小鼠AKI模型,PFT-α组于建模前5 min腹腔注射PFT-α  2.2 mg/kg,并于建模后48 h采血检测尿素氮和肌酐,取肾脏组织行HE染色观察肾组织病理学变化,采用Western blotting法测定P53蛋白含量,免疫荧光法确定肾脏不同部位P53的表达,TUNEL法检测肾脏细胞凋亡,免疫组化方法检测肿瘤坏死因子受体（TNFR）、caspase-3及Bcl-2蛋白水平 。结果：（1）PFT-α组和AKI组小鼠血尿素氮和肌酐水平均明显高于假手术组,而PFT-α组与AKI组比较血尿素氮和肌酐水平明显降低（P<0.05）;肾组织HE染色显示假手术组肾组织细胞形态完整,排列整齐,无明显病理改变,AKI组肾小管上皮细胞刷状缘脱落、空泡及滴状变性,皮髓质间有明显淤血带;PFT-α组肾小管上皮部分刷状缘脱落消失,空泡及滴状变性减轻,皮髓质间无明显淤血带;（2）假手术组小鼠肾脏有少量P53表达且未检测到凋亡细胞,而AKI组小鼠缺血再灌注48 h后P53蛋白水平及凋亡细胞明显增加（P<0.05）,并且均主要定位在肾皮质,PFT-α组较AKI组小鼠肾脏P53蛋白含量及凋亡细胞指数均减少（P<0.05）;（3）与假手术组相比,AKI组小鼠肾脏TNFR蛋白及caspase-3蛋白水平升高（P<0.05）,Bcl-2蛋白水平下降（P<0.05）,PFT-α组较AKI组小鼠肾脏TNFR蛋白及caspase-3蛋白水平降低（P<0.05）,Bcl-2蛋白水平升高（P<0.05）。结论：急性肾损伤时,肾组织P53表达增加,主要定位于皮质,通过调控凋亡蛋白Bcl-2和TNFR的水平,促进caspase-3的释放,从而介导细胞凋亡。     

肢体缺血再灌注后的肺损伤和细胞凋亡及NO的效应

目的：探讨肢体缺血再灌注（LIR）后肺的损伤性变化以及细胞凋亡在肺损伤发生中的作用；探讨一氧化氮（NO）对LIR后肺组织细胞凋亡的影响。 方法：采用本室常规方法复制大鼠LIR模型，给予外源性一氧化氮合酶底物（L-Arg）和一氧化氮合酶抑制剂(L-NAME)处理，采用原位末端标记法（TUNEL）检测缺血4 h再灌注4 h时各组动物肺组织细胞凋亡情况；采用放免法检测凋亡相关细胞因子TNF-α在肺组织的表达，结合计算机分析系统对结果进行定量分析；采用免疫组织化学方法检测Bcl-2、Bax、caspase-3、TNF-α蛋白表达情况，结合自动图像分析系统对其结果进行定量分析；在光镜下观察肺组织的形态学改变。结果：大鼠LIR后4 h，肺泡Ⅱ型上皮细胞、肺血管内皮细胞呈凋亡改变,肺组织TNF-α、caspase-3、Bax明显上调,Bcl-2表达下调。L-Arg处理组，凋亡细胞数明显减少，肺组织TNF-α、caspase-3、Bax的表达情况与IR组相比明显减弱，Bcl-2表达明显增强；L-NAME处理组动物肺组织TNF-α、caspase-3、Bax的表达情况与IR组相比明显增强，Bcl-2表达明显减弱。结论：细胞凋亡参与了大鼠LIR后急性肺损伤的发生，且与TNF-α有关；NO可通过减弱细胞凋亡相关因子TNF-α的表达，减轻LIR后肺组织的细胞凋亡。     

Caspase-12介导的内质网通路凋亡相关蛋白在大鼠肾发育中的表达

目的:探讨caspase-12介导的内质网通路凋亡相关蛋白在大鼠肾发育中的表达规律。方法:应用免疫组织化学显色与免疫印迹法,对大鼠肾发育中内质网通路凋亡相关蛋白caspase-12和cleaved-caspase-3的表达进行定性和定量观察。结果:免疫组织化学显示在大鼠肾发育中,caspase-12和cleaved-caspase-3的阳性表达由肾皮质区深层逐渐扩展到整个肾皮质区,其表达主要位于近端小管,而远端小管表达较微弱;免疫印迹结果显示在肾发育中,caspase-12被分解为cleavedcaspase-12,caspase-12和cleaved-caspase-12的蛋白表达在胚胎期较高,在生后(P)1 d达到高峰,随后其表达逐渐降低。而cleaved-caspase-3的蛋白表达在胚胎肾发育中较弱,在P1d其表达水平突然升高,随后维持在较高的水平。结论:Caspase-12介导的内质网通路凋亡相关蛋白可能参与大鼠胚胎肾发育中近端小管的细胞凋亡。     

抗β1-肾上腺素受体自身抗体对在体大鼠心肌细胞的致凋亡作用

目的：观察抗β1-肾上腺素受体（β1-AR）自身抗体对在体大鼠心肌细胞的致凋亡作用,并探讨其可能的信号转导通路,以阐明该抗体参与心衰发生发展的病理机制。方法：用β1-AR细胞外第二环合成肽段免疫抗β1-AR自身抗体阴性大鼠（9周）,定期检测大鼠的血清抗β1-AR自身抗体滴度、心功能、心肌组织凋亡现象和caspase-3,8,9活性。结果：（1）免疫组大鼠的血清抗β1-AR自身抗体滴度逐渐升高并维持于高水平[1∶（1280±0.07）];对照组始终在1∶10左右;（2）TUNEL和琼脂糖凝胶电泳显示免疫组大鼠在免疫3、4、5周心肌组织发生明显凋亡,caspase-3,8活性增高,免疫7、9周心功能明显下降,对照组未见异常。结论：抗β1-AR自身抗体可能通过激活死亡受体途径促进在体大鼠的心肌细胞发生凋亡,最终引起心功能下降。     

依赖天冬氨酸特异性半胱氨酸蛋白酶-3的肝细胞凋亡在肝硬化大鼠肝缺血再灌注损伤中的作用

目的:探讨肝硬化大鼠肝缺血/再灌注(I/R)损伤是否与肝细胞凋亡相关及天冬氨酸特异性半胱氨酸蛋白酶-3(caspase-3)活性变化与肝细胞凋亡的关系。方法:Pringle法复制肝I/R模型,将肝硬化大鼠随机分为2组:A组:单纯肝门阻断;B组:血流阻断+抑制剂:N-苯甲基氧化碳酰-缬氨酸-丙氨酸-天冬氨酸-氟化丙酮(ZVAD-fmk)15mg/kg;取无肝硬化大鼠,作单纯肝门阻断为C组。各组肝门阻断时间均为30min,再灌注72h。比较3组的血清天冬氨酸转氨酶(AST)、肝组织的caspase-3活性和肝细胞凋亡数。结果:A组大鼠肝组织caspase-3活性、肝细胞凋亡数在再灌注后6h达高峰,分别为(18.1±1.8)μmolAMC·h^-1·g^-1(tissue)和20.9%±4.9%,与I/R前的(6.6±2.0)μmolAMC·h^-1·g^-1(tissue)和0.5%±0.3%相比,P＜0.01。肝细胞凋亡数、caspase-3的活性随灌注时间的延长而减低,两者随时间的变化一致。3组中A组肝损伤最严重,表现为再灌注后6h血清AST最高,与B、C组比较有显著差异,大鼠7d生存率只为62.5%。进一步研究表明,再灌注后6h,A组的肝组织caspase-3活性、肝细胞凋亡数亦明显比B、C组高。结论:肝细胞凋亡是肝硬化大鼠肝I/R损伤的主要病理改变。肝细胞凋亡的发生可能主要依赖于肝组织caspase-3活性的改变,抑制caspase-3能明显减轻肝I/R损伤。肝硬化肝脏比无硬化肝脏对缺血损伤敏感性高的病理机制与依赖caspase-3的肝细胞凋亡密切相关。     

FAK反义寡核苷酸促进人肺动脉平滑肌细胞凋亡

目的： 了解黏着斑激酶(focal adhesion kinase FAK)是否参与人肺动脉平滑肌细胞(HPASMCs)凋亡。 方法： 纤黏连蛋白(FN 40 mg/L)刺激下培养的HPASMCs被用来进行反义寡核苷酸（antisense oligonucleotides， ASODNs）转染以做进一步实验。采用免疫印迹方法测定FAK蛋白质及凋亡蛋白半光氨酸蛋白酶－3（caspase-3）的表达, TUNEL法检测细胞凋亡。 结果： 免疫印迹方法测定结果表明,应用FAKASODNs转染后HPASMCs中FAK的表达明显低于转染前(P<0.01); caspase-3在应用FAKASODNs转染后高于转染前(P<0.05), TUNEL法检测结果表明FAKASODNs转染后细胞凋亡增加。 结论： 本实验结果表明FAKASODNs抑制细胞增生,促进细胞凋亡。其机制很可能是经caspase-3信号通路促进细胞凋亡。     

肝纤维化大鼠肝脏中内质网应激相关分子CHOP和TRB3的表达变化

 目的： 观察内质网应激相关分子CCAAT/增强子结合蛋白同源蛋白(CHOP）和Tribbles同源蛋白3（TRB3）在四氯化碳（CCl4）致大鼠肝纤维化过程中的表达变化,探讨其在肝纤维化过程中的可能作用。方法： 体重180～200　g的雄性Wistar大鼠随机分为正常4周组、正常8周组、肝纤维化4周组和肝纤维化8周组,肝纤维化组大鼠皮下注射40%CCl4制备肝纤维化模型,分别在4周和8周处死大鼠,观察肝组织病理改变,Western blotting检测肝脏活化转录因子6（ATF6）蛋白,免疫组化、Western blotting和real-time PCR分别检测肝脏CHOP和TRB3蛋白和mRNA表达变化,TUNEL法检测肝脏细胞凋亡。结果： 肝纤维化组大鼠肝脏可见假小叶形成,p90ATF6蛋白表达量较正常组明显减少（P<0.01）,p50ATF6蛋白表达量较正常组明显增加（P<0.01）,肝细胞胞浆CHOP和TRB3蛋白及mRNA表达量较正常组显著增加（P<0.01）,细胞凋亡率较正常组显著增加（P<0.01）。结论： 内质网应激相关分子CHOP和TRB3在CCl4致大鼠肝纤维化过程中蛋白及mRNA表达水平明显增加,其变化趋势与大鼠肝细胞凋亡率一致,提示内质网应激可能通过CHOP和TRB3促进肝细胞凋亡,参与肝纤维化发生发展。     

Hepatocyte Necroptosis Induced by Ischemic Acute Kidney Injury in Rats

Abstract

While ischemic acute kidney injury (IAKI) is known often to cause hepatic injury, little is known about necroptosis involved in the hepatic injury. The purposes of this study were to identify necroptosis involvement and observe morphological changes of hepatocytes in hepatic injury induced by IAKI in rats. Based on successfully established IAKI rat models, enzyme-linked immunosorbent assay illustrated a significant higher level of tumor necrosis factor a in serums of IAKI animals. Tumor necrosis factor receptor a (TNFRa) and receptor interacting protein kinase 3 (RIPk3) showed significant higher expressions in immunoblot analyses and positive hepatocytes of RIPk3 immunohistochemical staining were also evident in livers of IAKI rats. In addition, light microscopy revealed necrotic lesions that contain hepatocytes ongoing necroptosis besides necrotic cells in IAKI livers. Electron microscopy revealed at least three types of necrotic hepatocytes, they were edema necrosis, vacuolization necrosis, and necroptosis. Hepatocytes undergoing necroptosis had both necrosis and apoptosis morphological characteristics, they were necrosis cytoplasm and apoptosis-like nucleus. Among cellular organelles of hepatocyte with necrosis, membranous structures, such as cell membrane, endoplasmic reticular system, and mitochondria were more vulnerable to the stress of IAKI and deformed nucleuses varied in shape and lytic or pyknotic chromatin appearances were noted under insults of IAKI. In conclusion, hepatocyte undergoing necroptosis, RIPk3-mediated necroptosis partly contributes to hepatic necrosis induced by IAKI. Both membranous structures and nucleuses of hepatocyte were vulnerable to ischemic acute kidney injury.     

大鼠缺血性急性肾损伤对肺脏超微结构的影响

目的　观察大鼠缺血性急性肾损伤对肺脏细胞超微结构的影响。 方法　应用光学显微镜和透射电子显微镜技术以及立体计量学方法观察急性肾缺血60 min再灌注24 h后的肺脏。 结果　部分肺泡I型上皮细胞发生了肿胀性坏死,II型上皮细胞也出现了肿胀性坏死,细胞内大量空泡出现。嗜锇性板层小体消失,肺泡内皮细胞出现了凋亡的表现。肺内组织出现了中性粒细胞浸润。 结论　大鼠肾脏急性肾缺血损伤可引起肺细胞坏死与凋亡,其中坏死损伤为多见。此外,炎性细胞浸润也是不可忽略的症候。     

Inhibition of matrix metalloproteinases reduces ischemia-reperfusion acute kidney injury

Matrix metalloproteinases (MMPs) are endopeptidases that degrade extracellular matrix and involved in ischemic organ injuries. The present study was designed to determine the role of MMP-2 in the development of ischemic acute kidney injury (AKI). AKI was induced in MMP-2 wild-type (MMP-2(+/+)) mice by 30, 60, 90, and 120?min renal ischemia and reperfusion. Renal histology, expression and activity of MMP-2 and MMP-9, and renal function were examined during the development of AKI. AKI was also induced in MMP-2-deficient (MMP-2(-/-)) mice and MMP-2(+/+) mice treated with inhibitor of MMPs (minocycline and synthetic peptide MMP inhibitor). In MMP-2(+/+) mice, MMP-2 and MMP-9 activities increased significantly at 2 to 24?h, peaked at 6?h, after reperfusion. Immunohistochemical analysis identified MMP-2 in the interstitium around tubules and peritubular capillaries in the outer medulla. Acute tubular injury (ATI), including apoptosis and necrosis, was evident in the outer medulla at 24?h, along with renal dysfunction. As ischemia period increases, MMP-2 and MMP-9 activities at 6?h and severity of AKI at 24?h increased depending on the duration of ischemia between 30 and 120?min. However, the kidneys of MMP-2(-/-) mice showed minimal ATI; serum creatinine 24?h after reperfusion was significantly low in these mice. Inhibitors of MMPs reduced ATI and improved renal dysfunction at 24?h. We conclude that MMPs, especially MMP-2 have a pathogenic role in ischemia-reperfusion AKI, and that inhibitors of MMPs can protect against ischemic AKI.     

Apoptotic cell death in the response of D-galactosamine-sensitized mice to lipopolysaccharide as an experimental endotoxic shock model.

The apoptotic cell death induced in D-galactosamine-sensitized mice by administration of lipopolysaccharide was characterized. Administration of lipopolysaccharide caused apoptotic cell death in livers of D-galactosamine-sensitized mice. Apoptotic cells were also detected in the kidney, thymus, spleen, and lymph node. Severe hepatic apoptosis in D-galactosamine-sensitized mice was reproduced by transfer of the sera from mice injected with D-galactosamine and lipopolysaccharide. The hepatocyte apoptosis induced by lipopolysaccharide was completely prevented by an anti-tumor necrosis factor alpha antibody but not by an anti-gamma interferon antibody. Administration of recombinant tumor necrosis factor into D-galactosamine-sensitized mice also caused hepatocyte apoptosis. Lipopolysaccharide-induced hepatocyte apoptosis in D-galactosamine-sensitized mice did not seem to be mediated by Fas antigen. It was suggested that lipopolysaccharide- induced hepatic injury and failure in D-galactosamine-sensitized mice was due to the apoptotic cell death of hepatocytes caused by tumor necrosis factor alpha released in the circulation.     

Centrilobular endothelial cell injury by diquat in the selenium-deficient rat liver

Low doses of diquat cause massive liver necrosis and death of selenium-deficient rats within a few hours. Protection against this injury by selenium correlates with the presence of selenoprotein P, an extracellular selenoprotein that associates with endothelial cells. Selenium-deficient rats were injected with diquat (10 mg/kg) and their livers were removed for light and electron microscopy at times up to 120 minutes after injection. Selenium-replete animals were studied before and 120 minutes after the same dose of diquat. With selenium deficiency, diquat caused injury to centrilobular endothelial cells. This injury was evident 20 minutes after diquat injection and progressed to cell loss at 60 minutes after diquat injection. At 120 minutes, endothelial cells were virtually absent from the centrilobular regions and hepatocytes in those areas were undergoing necrosis. Portal and midzonal areas remained normal in selenium-deficient livers, as did the entire liver lobule of selenium-replete rats. These findings indicate that the initial liver lesion in selenium-deficient rats given diquat is injury of the endothelial cells in the centrilobular region. After detachment of the endothelial cells, centrilobular hepatocytes undergo necrosis. We postulate that selenoprotein P protects the centrilobular endothelial cells against injury by oxidant molecules that result from diquat administration.     

Chlordecone-induced potentiation of carbon tetrachloride hepatotoxicity: a light and electron microscopic study

Previous studies have shown that a chlorinated pesticide, chlordecone (Kepone), greatly potentiates carbon tetrachloride (CCl4) hepatotoxicity and lethality (Curtis, L.R., Williams, W.L., and Mehendale, H.M. (1979). Toxicol. Appl. Pharmacol. 51, 283-293; Curtis, L.R., and Mehendale, H.M. (1980). Drug Metab. Dispos. 8, 23-27). The present study describes sequential morphologic changes which occurred in livers of rats given a "nontoxic" level of chlordecone (10 ppm for 15 days) followed by a single injection of CCl4 (0.1 ml/kg). The hepatic alterations were examined 1 to 36 hr after exposure of the rats to CCl4. Those changes were compared to hepatic alterations which occurred in rats that received the same dose of chlordecone (10 ppm for 15 days) or a single injection of CClr (0.1 ml/kg) alone. The only change noted in livers from rats that received chlordecone alone was focal increase in smooth endoplasmic reticulum (SER) of hepatocytes at 24 hr and continuing throughout the time course of the experiment. Livers from animals that received CCl4 alone showed morphologic changes at 6 hr consisting of glycogen loss, increase in SER, and dilatation of rough endoplasmic reticulum (RER) in pericentral hepatocytes. Accumulation of small lipid droplets was also noted in midzonal hepatocytes. After 6 hr, there was no further increase in severity of injury. At 12 hr recovery was noticeable and, by 36 hr, livers from the CCl4 group appeared normal. Prior administration of chlordecone greatly potentiated pathologic changes in livers of animals that received CCl4. By 4 hr, there was total loss of glycogen in hepatocytes throughout the entire lobule. Small lipid droplets were present in pericentral, midzonal and periportal hepatocytes. Hepatocytes with extremely dilated RER were randomly scattered throughout the entire lobule. At 6 hr, there was further accumulation of lipid in the form of large droplets in hepatocytes. Focal, necrotic cells surrounded by polymorphonuclear leukocytes were randomly distributed throughout the lobule. The number of necrotic foci had progressively increased at the 12- and 24-hr intervals. By 36 hr, confluent areas of necrosis in pericentral and midzonal areas were observed in livers of some animals. This study indicates that although the combination of chlordecone and CCl4 produces much greater hepatic injury resembling damage due to a massive dose of CCl4, histologically, some differences in the progression and distribution of hepatocellular damage within the lobular architecture of the liver are evident.     

Chlordecone-induced potentiation of carbon tetrachloride hepatotoxicity: a morphometric and biochemical study

The present study, conducted over a time course of 36 hr after CCl4 administration, describes sequential morphometric and biochemical changes which occur in livers of rats exposed to a combination of low levels of chlordecone (10 ppm for 15 days) and a single ip injection of CCl4 (0.1 ml/kg). Those changes were compared to hepatic alterations which occur in rats that received the same dose of chlordecone or CCl4 alone. Biochemical studies showed only trivial increases in levels of glutamic-pyruvic transaminase (GPT), glutamic-oxalacetic transaminase (GOT), and moderate but temporary increases in isocitrate dehydrogenase (ICD) after CCl4 alone. The combination of chlordecone and CCl4 resulted in significantly greater elevations of all three serum enzymes at all time intervals examined. Morphometric data showed no difference between normal diet controls and animals exposed to chlordecone alone as far as numerical density of hepatocytes or volume densities of hepatocytes with glycogen, lipid, dilated rough endoplasmic reticulum (RER), pyknosis, or mitoses. Morphometric analysis of livers from animals that received CCl4 alone showed decreases in numerical density, temporary decrease in percentage of hepatocytes containing glycogen, an increase in hepatocytes containing lipid, temporary increase in hepatocytes with dilated RER, and temporary increases in pyknotic nuclei. Soon after the initial hepatic injury was histologically evident between 4 and 6 hr, the number of mitoses increased dramatically and this progressed until complete recovery from CCl4 damage. From all indices of damage, complete recovery was evident by 36 hr after CCl4 administration.(ABSTRACT TRUNCATED AT 250 WORDS)