黄芪对脑缺血-再灌注后神经细胞凋亡及凋亡相关基因表达的影响

目的:探讨黄芪对脑缺血-再灌注后神经细胞凋亡及凋亡相关基因Bcl-2、Fas-L蛋白表达的影响.方法:采用Longa报道的线栓法制备大鼠局灶性脑缺血-再灌注模型.将36只SD大鼠随机分为假手术组(生理盐水10 ml·kg-1·d-1灌胃)、模型组(生理盐水10 ml·kg-1·d-1灌胃)和黄芪干预组(黄芪煎剂6 g·kg-1·d-1灌胃),每组12只.采用末端脱氧核苷酸转移酶介导的生物素化脱氧尿嘧啶缺刻标记技术(TUNEL)检测各组大鼠脑组织神经细胞凋亡,免疫组化与医学图像分析结合的方法检测Bcl-2、Fas-L蛋白的表达.结果:与假手术组相比,模型组大鼠缺血侧脑组织TUNEL阳性神经细胞及Bcl-2、FasL阳性细胞表达增多(P均<0.01).与模型组相比,黄芪干预组大鼠缺血侧脑组织TUNEL阳性神经细胞及Fas-L阳性细胞表达减少,Bcl-2阳性细胞表达增多(P<0.01).结论:黄芪可增强Bcl-2蛋白表达,下调Fas-L蛋白表达,从而抑制脑缺血-再灌注后神经细胞凋亡,这可能是黄芪对脑缺血-再灌注损伤的神经保护作用机制之一.     

Hepatocyte apoptosis is enhanced after ischemia/reperfusion in the steatotic liver

Liver steatosis is associated with organ dysfunction after hepatic resection and transplantation which may be caused by hepatic ischemia/reperfusion injury. The aim of the current study was to determine the precise mechanism leading to hepatocyte apoptosis after steatotic liver ischemia/reperfusion. Using a murine model of partial hepatic ischemia for 90 min, we examined the levels and pathway of apoptosis, and the peroxynitrite expression, serum alanine aminotransferase levels, and liver histology 1 and 4 h after reperfusion. In the steatotic liver, the peroxynitrite expression increased after ischemia/reperfusion. Significant hepatocyte apoptosis in the steatotic liver was seen after reperfusion, caused by upregulation of cleaved caspases 9 and 3, but not caspase 8. Serum alanine aminotransferase levels were elevated and histological examination revealed severe liver injury in the steatotic liver 4 h after reperfusion. In mice treated with aminoguanidine, ischemia/reperfusion-induced increases in serum alanine aminotransferase levels and apoptosis were significantly reduced in steatotic liver compared with mice treated with phosphate buffered saline. Survival of mice with steatotic livers significantly improved by treatment with aminoguanidine. Our data suggested that the steatotic liver is vulnerable to hepatic ischemia/reperfusion, leading to significant hepatocyte apoptosis by the mitochondrial permeability transition, and thereby resulting in organ dysfunction.     

抗氧化剂在降低肝缺血再灌注损伤中的作用

肝移植、肝部分切除、缺血性休克等往往引起临床上肝脏缺血再灌注损伤,在这些过程中一个显著的特征就是氧化应激反应的发生并伴有内源性抗氧化剂的缺失.机体内复杂的抗氧化系统包括细胞内的酶类或非酶类的自由基清除剂以及饮食中的物质等.采用抗氧化剂治疗可以降低肝缺血再灌注损伤,关且当某些外科策略如缺血预处理不能实施时,药物治疗就显示出独特的优势.近年来,在肝缺血再灌注损伤治疗上有一些新的发展,如超氧化物歧化酶衍生物、含巯基化合物、选择性一氧化氮合酶抑制剂的出现及基因治疗等,多在一定程度上降低了肝缺血再灌注损伤的程度.     

吗啡对大鼠肝脏缺血再灌注损伤的影响

目的:缺血再灌注是肝脏手术和肝移植术中不可避免的病理过程,吗啡对于心肌缺血再灌注损伤以及对抗心肌细胞凋亡等方面已有了很大的研究进展.观察吗啡对大鼠肝缺血再灌注损伤的影响,并分析其可能作用途径.方法:实验于2006-08/2007-03在辽宁医学院附属医院外科实验室完成,动物实验方法符合动物伦理学要求.①实验分组及方法:选用Wistar大鼠60只,按随机数字表法分成4组(n=15),正常对照组、假手术组、缺血再灌注组及缺血再灌注 吗啡干预组,缺血再灌注组建立大鼠肝脏缺血再灌注损伤模型;缺血再灌注 吗啡组于缺血再灌注前给予0.3 mg/kg盐酸吗啡注射液腹腔内注射.②实验评估:于再灌注90 min后,各组大鼠经左心室取血,测定血浆中谷丙转氨酶、谷草转氨酶活性;取肝脏组织,应用流式细胞仪检测肝细胞凋亡率,应用免疫组化法检测半胱氨酸蛋白酶3的表达变化.结果:60只大鼠均进入结果分析.①血浆谷丙转氨酶、谷草转氨酶活性:缺血再灌注组显著高于正常对照组和假手术组(P＜0.01),吗啡 缺血再灌注组显著低于缺血再灌注组(P＜0.01).②肝细胞凋亡率:缺血再灌注组显著高于正常对照组和假手术组(P＜0.01),吗啡 缺血再灌注组显著低于缺血再灌注组(P＜0.01).③肝脏组织半胱氨酸蛋白酶3的表达:缺血再灌注组显著高于正常对照组和假手术组(P＜0.01),吗啡 缺血再灌注组显著低于缺血再灌注组(P＜0.01).结论:吗啡可抑制缺血再灌注损伤后肝细胞的凋亡,减轻肝脏的损伤,从而起到保护肝脏的作用.     

大鼠局灶性脑缺血再灌注后fas基因和fasL基因表达变化的规律

目的:探讨大鼠局灶性脑缺血再灌注后FasmRNA和FasLmRNA的表达变化。方法:实验于2004-03-01/06-30在哈尔滨医科大学附属第二医院科研中心进行。取健康Wister大鼠48只随机分为6组,即假手术组,缺血2h再灌注6,12,24,48和72h组,每组8只鼠。线栓法建立大鼠大脑中动脉闭塞(MCAO)及再通模型,应用RT-PCR技术检测MCAO及再通后缺血半暗带皮质FasmRNA和FasLmRNA表达。结果:假手术组FasmRNA,FasLmRNA均未见表达,再灌注6h起二者开始有少量表达(分别为0.23±0.02和0.06±0.01),FasmRNA的表达高峰在再灌注24h(0.94±0.06),FasLmRNA的表达高峰在再灌注48h(0.35±0.02),再灌注72h二者的表达均明显下降(分别为0.45±0.03和0.22±0.03)。结论:脑缺血再灌注可诱导FasmRNA和FasLmRNA表达。     

潘生丁预处理对大鼠肝缺血/再灌注损伤的保护作用

目的探讨潘生丁预处理对肝缺血／再灌注损伤的保护作用。方法 SD大鼠30只，随机分为假手术组、缺血／再灌注组及潘生丁组，每组10只。常温下制备大鼠肝缺血／再灌注损伤模型，潘生丁组于缺血前30min经门静脉给予潘生丁10mg／kg加生理盐水至0．5ml，假手术组和缺血／再灌注组注人等量生理盐水，用小号无损伤钳阻断肝门45min后恢复血流灌注，并于1h后取门静脉血测定血清丙氨酸转氨酶（ALT）、乳酸脱氢酶（LDH）、肿瘤坏死因子-α（TNF-Ⅱ）及内皮素-1（ET-1），同时取肝组织行病理组织学检查及腺苷酸含量测定。结果缺血／再灌注组血清ALT、LDH、TNF-α及ET-1均明显高于假手术组，潘生丁组则明显低于缺血／再灌注组（P均〈O．01）。缺血／再灌注组肝组织中腺苷酸含量明显低于假手术组，潘生丁组则明显高于缺血／再灌注组（P均〈O．01）。潘生丁组肝组织病理组织学改变明显轻于缺血／再灌注组，并接近假手术组。结论潘生丁预处理对肝缺血／再灌注损伤具有保护作用。     

生长激素对大鼠心肌缺血/再灌注后心肌细胞凋亡及凋亡相关基因NF-κB蛋白表达的影响

目的　研究生长激素 (growthhormone ,GH)对大鼠心肌缺血 /再灌注 (IR)后心肌细胞凋亡及相关基因NF -κB蛋白表达的影响。方法　 2 4只大鼠随机分为 3组 ,假手术组 (n =8,仅手术 2 4h)、心肌缺血 /再灌注 (IR)组 (n =8)、GH组 (n =8) ,后两组均缺血 30min ,再灌注 2 4h ,其中GH组的每只大鼠实验术前皮下肌注GH 1U/kg体重 ,连续 7d ,其中第 7次皮下注射于手术前进行。前两组每只大鼠相应皮下肌注生理盐水 0 .5mL/d。检测心肌细胞凋亡及心肌细胞核NF -κB蛋白表达并进行心肌组织病理学检查。结果　大鼠心肌IR 2 4h后心肌细胞凋亡指数明显上升 (对照于假手术组 ,P <0 .0 5 ) ,心肌细胞核NF -κB蛋白表达呈阳性染色指数明显升高 (P <0 .0 5 ) ,心肌病理检查见心肌缺血区呈大小不一的坏死孔灶 ,缺血心肌间有炎症细胞浸润 ,心肌排列不整齐 (HE染色 ) ,而GH组心肌细胞凋亡率及心肌细胞核NF -κB蛋白表达呈阳性染色指数明显好于IR组 (P <0 .0 5 ) ,心肌细胞炎症细胞也明显减少 ,坏死灶也少于IR组。结论　GH可以减少心肌缺血 /再灌注后心肌细胞凋亡及细胞核NF -κB染色阳性指数 ,说明GH对IR后的心肌具有保护作用     

Altered endothelin receptor subtype expression in hepatic injury after ischemia/reperfusion

This study was performed to determine whether ischemia/reperfusion (I/R) injury in rat liver results in alterations in endothelin receptor expression. Hepatic ischemia was produced in rats for 60 min followed by 6 or 24 h reperfusion. Portal inflow pressure was increased (7.38+/-0.60 mmHg) at 24 hours after reperfusion. Serum ALT increased significantly at both 6 and 24 h (6 h; 258.3+/-74.3, 24 h; 243.1+/-74.8 IU/L). Portal vascular response to an endothelin-B receptor agonist (IRL 1620) was significantly increased in the I/R livers compared to control and this was potentiated by L-NAME. IRL 1620 also caused LDH release from I/R livers but not controls. LDH release after IRL 1620 in I/R livers correlated with increased portal pressure response. To determine whether the altered response might be the result of altered endothelin receptor expression, livers were harvested after reperfusion and total endothelin binding sites were determined by competitive binding with ET-1. Proportion of endothelin receptor subtypes (ET(A)/ET(B)) was determined using the ET(A) antagonist BQ-610 (1 microM) and ET(B) agonist IRL-1620 (100 nM). There were no significant changes in Kd but Bmax for endothelin-1 was decreased in I/R group especially non-ischemic lobe at 24 h. ET(A) receptors were significantly decreased whereas ET(B) receptors were increased. These changes were more pronounced at 24 h after reperfusion than at 6 h. Interestingly, the changes in ET receptors was observed identically both in ischemic and non-ischemic lobes (ischemic lobe ET(A) 41.9%, ET(B) 51%; non-ischemic lobe ET(A) 38.8%, ET(B) 49.5%). These results indicate that the major functional endothelin receptor subtype upregulated in I/R is the ET(B) receptor and that this upregulation may contribute to microvascular dysregulation and hepatic injury.     

A complement-dependent balance between hepatic ischemia/reperfusion injury and liver regeneration in mice

Massive liver resection and small-for-size liver transplantation pose a therapeutic challenge, due to increased susceptibility of the remnant/graft to ischemia reperfusion injury (IRI) and impaired regeneration. We investigated the dual role of complement in IRI versus regeneration in mice. Complement component 3 (C3) deficiency and complement inhibition with complement receptor 2–complement receptor 1–related protein y (CR2-Crry, an inhibitor of C3 activation) provided protection from hepatic IRI, and while C3 deficiency also impaired liver regeneration following partial hepatectomy (PHx), the effect of CR2-Crry in this context was dose dependent. In a combined model of IRI and PHx, either C3 deficiency or high-dose CR2-Crry resulted in steatosis, severe hepatic injury, and high mortality, whereas low-dose CR2-Crry was protective and actually increased hepatic proliferative responses relative to control mice. Reconstitution experiments revealed an important role for the C3a degradation product acylation-stimulating protein (ASP) in the balance between inflammation/injury versus regeneration. Furthermore, liver regeneration was dependent on the putative ASP receptor, C5L2. Several potential mechanisms of hepatoprotection and recovery were identified in mice treated with low-dose CR2-Crry, including enhanced IL-6 expression and STAT3 activation, reduced hepatic ATP depletion, and attenuated oxidative stress. These data indicate that a threshold of complement activation, involving ASP and C5L2, promotes liver regeneration and suggest a balance between complement-dependent injury and regeneration.     

自噬与缺血再灌注损伤

自噬是存在于真核细胞生物中的一种细胞自我吞噬的现象。在生理状态下,可以维持机体内环境的稳定。在多种疾病的发生过程中,自噬也发挥重要作用。实验证明在缺血再灌注损伤的整个过程中,均有自噬的参与,但在缺血阶段和再灌注阶段,自噬有可能发挥不同的作用。在缺血阶段,自噬发挥保护细胞的作用,而在再灌注阶段,自噬可能会进一步加重细胞损伤甚至导致细胞死亡。     

甲状腺素预处理对大鼠肝脏缺血／再灌注后热休克蛋白70表达的信号研究

目的探讨甲状腺素能否通过对PI3 K-Akt信号通路的活化,上调热休克蛋白70（HSP70）,对缺血/再灌注（ischemia/reperfusion, I/R）损伤的大鼠肝脏发挥保护作用。方法建立大鼠肝脏I/R模型（缺血30 min,再灌注48 h）,将雌性Wistar大鼠随机分为假手术组、I/R组和处理组。处理方法为缺血前48 h于腹腔注射0．1 mg/kg甲状腺素。再灌注后检测肝组织丙二醛（ MDA）含量,血清肿瘤坏死因子-α（ TNF-α）、丙氨酸转氨酶（ ALT）和天冬氨酸转氨酶（ AST）浓度,用蛋白质免疫印迹法检测肝组织HSP70含量表达、总Akt、磷酸化Akt（ P-Akt）水平。结果与假手术组比较,I/R组血中ALT、AST、TNF-α和MDA含量均显著升高（ P＜0．05）。与I/R组比较,处理组各指标水平均显著降低,但较假手术组高（P＜0．05）。假手术组有少量HSP70和磷酸化Akt表达,处理组HSP70表达及Akt磷酸化水平均高于I/R组（P＜0．05）。结论甲状腺素可能通过PI3K-Akt信号通路诱导多量HSP70表达,在大鼠肝脏I/R损伤中发挥细胞保护的作用。     

Somatostatin infusion increases intestinal ischemia and does not improve vasoconstrictor response to norepinephrine in ovine endotoxemia

Hemodynamic support of patients with septic shock is often complicated by a tachyphylaxis against exogenous catecholamines. Because an increase in somatotropic hormones may play a pivotal role in the regulation of the inflammatory response to endotoxin, intravenous supplementation of the neuroendocrine hormone somatostatin (SOMA) may attenuate hemodynamic dysfunction resulting from endotoxemia. The objective of the present study was to assess the short-term effects of SOMA alone and in combination with norepinephrine (NE) on cardiopulmonary hemodynamics, global oxygen transport, plasma nitrate/nitrite levels, and intestinal integrity compared with single NE therapy in ovine endotoxemia. After a baseline measurement in healthy sheep (n = 16) had been performed, Salmonella typhosa endotoxin was centrally infused (10 ng x kg(-1) x min(-1)) to induce a hypotensive-hyperdynamic circulation using an established protocol. Animals surviving 16 h of endotoxemia were randomly assigned to one of the two groups (each n = 6). Sheep allocated to the SOMA + NE group received SOMA as a loading dose of 10.5 microg x kg(-1) x min(-1) for 1 h, followed by a continuous infusion of 3.5 microg x kg(-1) x min(-1) for the next 2 h. After the SOMA loading dose had been given, NE was concurrently infused (0.3 microg x kg(-1) x min(-1)) for 2 h. In the NE group (control), NE (0.3 microg x kg(-1) x min(-1)) was continuously infused for 3 h. Endotoxemia caused a decrease in MAP and systemic vascular resistance index in both groups, but to a greater extent in the NE group. Arterial hypotension persisted despite administration of the study drugs. Infusion of SOMA alone and in combination with NE did not significantly increase systemic vascular resistance index. Neither SOMA nor NE infusion alone affected pulmonary vasoregulation. Plasma nitrate/nitrite levels did not differ between groups. However, combined infusion of SOMA and NE significantly increased arterial lactate concentrations, oxygen consumption index, and oxygen extraction rate (P < 0.05) and aggravated ileal mucosal injury. In conclusion, short-term treatment with SOMA failed to attenuate cardiocirculatory shock resulting from endotoxemia and did not improve vasopressor response to NE. In addition, combined SOMA and NE therapy resulted in intestinal injury. Therefore, SOMA does not seem to represent a therapeutic option to treat arterial hypotension resulting from sepsis and systemic inflammatory response syndrome.     

c-fos and c-jun mRNA expression in a pig liver model of ischemia/reperfusion: effect of extended cold storage and the antioxidant idebenone

OBJECTIVES: Expression of immediate early genes has been reported during reperfusion after ischemia in rat livers due to oxygen radical formation. This study investigates in perfused pig livers the effect of the antioxidant idebenone and of cold ischemia time on the gene expression of c-fos and c-jun. DESIGN AND METHODS: Livers were perfused for 210 min after 0.5 h or 20 h ischemic storage (4 degrees C). One group of pigs was fed idebenone (280 mg/day/7days) prior to organ harvesting. C-fos and c-jun mRNA were determined by RT-PCR at 3, 30, 60, 120 180, 210 min during reperfusion. RESULTS: Lipid peroxidation increased in liver tissue form 0.54 +/- 0.21 to 1. 09 +/- 0.54 nmol MDA/mg protein during reperfusion after 20 h compared to 0.5 h cold storage. This was antagonized by idebenone (0. 68 +/- 0.20 nmol/MDA/mg protein). C-fos and c-jun were strongly induced in livers stored for 20 h, which was attenuated by idebenone (p < 0.05). CONCLUSIONS: These findings suggest that cold ischemia time and oxygen radicals are critical for immediate early gene expression and that application of an effective antioxidant can attenuate this early stress reaction of the pig liver.     

糖调节蛋白78在缺血/再灌注损伤心肌中表达的意义

热休克蛋白70(HSP70)是广泛存在于原核和真核生物细胞内的一种蛋白质,其基本功能为帮助新生蛋白质的正确折叠、移位、维持,以及受损蛋白质的修复、移除、降解,对肾脏等组织器官缺血/再灌注(I/R)损伤具有保护作用[1].糖调节蛋白78(GRP78)也叫免疫球蛋白重链结合蛋白,因与HSP70家族具有高度同源性,而被认为是HSP70家族成员之一.GRP78能抑制细胞毒性,对抗细胞凋亡,是维持胚胎细胞生长和潜能细胞存活的必备物质基础[2].GRP78在多种组织I/R损伤中表达上调,对心肌细胞的存活具有重要的保护作用[3].目前国内关于缺血预处理(IP)对I/R损伤心肌中GRP78表达变化的影响尚未见报道,本实验旨在观察IP对GRP78表达的影响,以期为心肌I/R损伤的研究和临床干预性治疗提供实验依据.     

人参和氯沙坦对缺血再灌注心肌细胞Bcl-2表达的影响

背景心肌细胞凋亡与缺血再灌注损伤直接相关,Bcl-2表达与细胞凋亡密切相关.临床和实验证实人参和氯沙坦均能改善心肌缺血,对缺血再灌注损伤有明显保护作用,但两者对缺血再灌注心肌细胞损伤有何异同?目的探讨人参和氯沙坦对大鼠缺血再灌注心肌细胞内Bcl-2 mRNA和蛋白质表达的影响.设计随机对照实验.单位华中科技大学同济医学院附属同济医院心血管内科,华中科技大学同济医学院神经生物学系.材料实验于2002-11/2003-04在华中科技大学同济医学院附属同济医院心血管内科实验室完成.采用健康成年Wistar大鼠40只,体质量200～250 g,雌雄不限,随机分为假手术对照组,缺血再灌注组,人参治疗组和氯沙坦治疗组,每组10只.方法缺血再灌注组,人参治疗组和氯沙坦治疗组均造模,假手术对照组不造模.氯沙坦治疗组术前2 h,术后立即和术后24h分别给予氯沙坦20 mg/kg(1 mL),灌胃各1次;人参治疗组术前2 h,术后立即和术后24 h分别给予红参煎剂(1 g/mL,1 mL/次)灌胃各1次.假手术对照组和缺血再灌注组分别于相同时间给予相同容积的生理盐水灌胃.用原位杂交和免疫组化分别检测人参和氯沙坦治疗后的大鼠缺血再灌注心肌细胞内Bcl-2 mRNA和蛋白质含量,并与对照组比较.主要观察指标人参和氯沙坦治疗后的大鼠缺血再灌注心肌细胞内Bcl-2mRNA和蛋白质的表达水平,并与对照组比较.结果实验大鼠40只均进人结果分析.①氯沙坦组与对照组心肌细胞内Bcl-2 mRNA,蛋白含量无明显差别(P＞0.05).②人参治疗组Bcl-2mRNA含量和Bcl-2蛋白表达高于缺血再灌注组(P＜0.05或0.01).结论人参治疗组Bcl-2 mRNA及Bcl-2蛋白表达均较氯沙坦治疗组高,提示人参防治心肌缺血再灌注损伤抑制心肌细胞凋亡与氯沙坦不同.     

人参和氯沙坦对缺血再灌注心肌细胞Bcl-2表达的影响

背景：心肌细胞凋亡与缺血再灌注损伤直接相关，Bcl-2表达与细胞凋亡密切相关。临床和实验证实人参和氯沙坦均能改善心肌缺血，对缺血再灌注损伤有明显保护作用，但两者对缺血再灌注心肌细胞损伤有何异同？目的：探讨人参和氯沙坦对大鼠缺血再灌注心肌细胞内Bcl-2mRNA和蛋白质表达的影响。设计：随机对照实验。单位：华中科技大学同济医学院附属同济医院心血管内科，华中科技大学同济医学院神经生物学系。材料：实验于2002-11／2003—04在华中科技大学同济医学院附属同济医院心血管内科实验室完成。采用健康成年Wistar大鼠40只，体质量200-250g，雌雄不限，随机分为假手术对照组，缺血再灌注组，人参治疗组和氯沙坦治疗组，每组10只。方法：缺血再灌注组，人参治疗组和氯沙坦治疗组均造模，假手术对照组不造模。氯沙坦治疗组术前2h，术后立即和术后24h分别给予氯沙坦20mg／kg（1mL），灌胃各1次；人参治疗组术前2h，术后立即和术后24h分别给予红参煎剂（1g／mL,1mL／次）灌胃各1次。假手术对照组和缺血再灌注组分别于相同时间给予相同容积的生理盐水灌胃。用原位杂交和免疫组化分别检测人参和氯沙坦治疗后的大鼠缺血再灌注心肌细胞内Bcl-2mRNA和蛋白质含量，并与对照组比较。主要观素指标：人参和氯沙坦治疗后的大鼠缺血再灌注心肌细胞内Bcl-2mRNA和蛋白质的表达水平，并与对照组比较。结果：实验大鼠40只均进人结果分析。①氯沙坦组与对照组心肌细胞内Bcl-2mRNA，蛋白含量无明显差别（P〉0．05）。②人参治疗组Bcl-2mRNA含量和Bcl-2蛋白表达高于缺血再灌注组（P〈0．05或0．01）。结论：人参治疗组Bcl-2mRNA及Bcl-2蛋白表达均较氯沙坦治疗组高，提示人参防治心肌缺血再灌注损伤抑制心肌细胞凋亡与氯沙坦不同。     

Effects of endotoxin tolerance on liver function after hepatic ischemia/reperfusion injury in the rat

OBJECTIVE: It is known that endotoxin tolerance prevents lethality after ischemia/reperfusion injuries (e.g., myocardial infarction) in laboratory animals. We used a rat model of partial hepatic ischemia/reperfusion to investigate whether endotoxin tolerance prevents associated lethality and disorders of liver function. DESIGN: Prospective animal study. SETTING: University research facility. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Hepatic ischemia was initiated by atraumatic clipping across the portal venous and hepatic arterial blood supply to the left lateral lobe for 90 mins. The common bile duct was canalized, and in a second set of experiments the bile duct of the left lateral lobe was canalized selectively. Bile flow, bile acids, and transaminases were determined during ischemia and 300 mins of reperfusion in endotoxin-tolerant and -nontolerant rats. MEASUREMENTS AND MAIN RESULTS: Endotoxin-nontolerant animals showed a 50% lethality after hepatic ischemia/reperfusion injuries. All endotoxin-tolerant rats survived and did not react with any change in bile flow, showing a constant flow. The amount of bile acids in the common bile duct was reduced during ischemia and regained the concentrations of sham-operated animals 60 mins after reperfusion. From 180 mins after reperfusion, the difference between endotoxin-tolerant and -nontolerant animals was statistically significant. When bile acid concentration was determined in the ischemic left lateral lobe, ischemia/reperfusion was found to significantly decrease in endotoxin-nontolerant rats 60 mins after reperfusion. In contrast, endotoxin-tolerant rats produced normal amounts of bile acids 60 mins after reperfusion. At 120 mins after reperfusion, the amount of bile acids in the formerly ischemic left lateral lobe was more than normal. CONCLUSIONS: In this model of partial hepatic ischemia/reperfusion, endotoxin tolerance prevents ischemia/reperfusion injury-associated lethality and local disorders of liver function. This phenomenon induced by endotoxin tolerance may be useful in liver surgery to prevent ischemia/reperfusion injury.