乌司他丁对肝缺血-再灌注损伤保护作用的研究进展

肝缺血-再灌注损伤(ischemia reperfusion injury,IRI)是指肝脏组织在缺血一段时间后血流重新恢复,体内代谢急剧变化,从而使肝脏代谢功能及结构进一步遭到破坏,常见于肝移植、肝脏严重创伤性手术以及肝脏部分切除等情况[1].肝IRI不仅是肝移植术后移植肝功能不全或无功能和肝切除术后肝衰竭的主要原因,也是导致肝移植后发生急性和慢性排斥反应的重要因素之一.     

乌司他丁对大鼠全肝缺血-再灌注肺损伤的保护作用

目的 观察乌司他丁对大鼠全肝缺血-再灌注(I-R)肺损伤的保护作用.方法 24只SD大鼠随机分为全肝缺血-再灌注组(I-R组)、乌司他丁组(U组)及假手术对照组(C组),每组8只.检测支气管肺泡灌洗液(BALF)中总蛋白含量、肺组织干/湿质量比(D/W)、肺组织髓过氧化物酶(MPO)及超氧化物歧化酶(SOD)含量,并以逆转录聚合酶链式反应(RT-PCR)方法检测三组大鼠肺组织基质金属蛋白酶(MMP)14 mRNA的相对表达量.结果 与U组和C组比较,I-R组大鼠肺组织BALF总蛋白和MPO含量明显增高,肺组织D/W和SOD显著降低.MMP14 mRNA相对表达量显著增高(P<0.05).结论 乌司他丁可减轻全肝I-R肺损伤;抑制肺组织MMP14 mRNA的表达可能是其机制之一.     

川芎嗪联合乌司他丁对断肢再植缺血再灌注损伤的保护作用

目的：评价川芎嗪和乌司他丁对断肢再植缺血再灌注损伤的保护作用。方法：40例上肢离断再植病人,随机分为4组,A组为对照组,围手术期不接受川芎嗪和乌司他丁。B组为乌司他丁组,于再植后动脉开放前给予乌司他丁0.5万U/kg。C组为川芎嗪组,于再植后动脉开放前给予川芎嗪2.5 mg/kg。D组为联合组,于再植后动脉开放前分别给予乌司他丁0.5万U/kg、川芎嗪2.5 mg/kg。分别于术前（T1）、术中再灌注后30 min（T2）,术后3 h（T3）、24 h（T4）、72 h（T5）共5个时点采集中心静脉血,测定患者血清天冬氨酸氨基转移酶（AST）、肌酸激酶（CK）、乳酸脱氢酶（LDH）、丙二醛（MDA）和超氧化歧化酶（SOD）的含量在该过程中的变化。结果：血清AST、CK、MDA的含量在A组、B组、C组有升高趋势,与A组比较,B、C组的AST、CK在不同时点上升幅度较小,有显著性差异（P〈0.05）。D组无明显上升,有非常显著性差异（P〈0.01）。血清LDH的含量在A组有上升趋势,B、C、D组无明显上升,与A组比较在T2时点有显著性差异（P〈0.05）。血清SOD的含量在A、B、C组有降低趋势,B、C组下降幅度较小,与A组比较有显著性差异（P〈0.05）。D组无明显下降,与A组比较有非常显著性差异（P〈0.01）。结论：川芎嗪和乌司他丁对断肢再植缺血再灌注损伤具有一定的保护作用,联合使用效果更佳。     

乌司他丁联合异甘草酸镁对肝脏缺血再灌注损伤的保护作用

目的探讨乌司他丁联合异甘草酸镁对人肝脏缺血再灌注损伤的保护作用。方法选取60例需行肝叶切除手术的患者,随机分为对照组(单用乌司他丁)28例和试验组(乌司他丁联用异甘草酸镁)32例。观察术前及术后1 d、3 d、7 d两组谷丙转氨酶(ALT)、谷草转氨酶(AST)、血浆丙二醛(MDA)和超氧化物岐化酶(SOD)水平。结果术后l d、3 d、7 d,联用组与对照组在ALT、AST、MDA、SOD水平上差异均具有统计学差异(P0.05)。结论乌司他丁联合异甘草酸镁对人肝脏缺血再灌注损伤具有明显的协同保护作用。     

乌司他丁对心脏直视术中缺血-再灌注损伤的保护作用

目的：研究乌司他丁对心肺转流（CPB）心脏直视手术中缺血－再灌注损伤的保护作用。方法：20例择期CPB心脏瓣膜手术患者随机均分为对照组（C组）和乌司他丁组（U组），C组不给药，U组给予乌司他丁100万U（其中30万U为麻醉诱导前给予，40万U预充体外循环机内，30万U为开放升主动脉后给予），分别于麻醉诱导后（T1），阻断升主动脉30分钟（T2），再灌注1小时（T3），再灌注2小时（T4）及再灌注3小时（T5）各时间点取静脉血用ELISA法测定样本中下降各指标的水平。肿瘤坏死因子－α（TNF-α），白细胞介素－6（IL－6），白细胞介素－8（IL－8）。结果：两组血清中TNF－α，IL-6，IL－8的浓度，都是在再灌注后与手术前值及阻断主动脉30分钟的值相比有明显的增加（P＜0．05），在T3，T4，T5三个时点C组的TNF－α，IL－6，IL－8的释放明显低于对照组（P＜0．05），结论：在CPB过程中乌司他丁可以通过抑制炎性介质TNF－α，IL－6和IL－8的释放而减轻缺血－再灌注损伤。     

乌司他丁对大鼠胰腺缺血再灌注损伤的保护作用

目的探讨乌司他丁对大鼠胰腺缺血再灌注损伤的保护作用及其机制。方法SD大鼠72只随机分为假手术组（C）、缺血再灌注组（I）和乌司他丁组（U）。采用ELISA和免疫组化方法检测大鼠血清中肿瘤坏死因子α（TNF-α）、白细胞介素1B（IL-1β）、胰腺组织bcl-2蛋白和热休克蛋白70（HSP70）表达的变化;并观察胰腺病理组织学改变。结果缺血再灌注组的各时点TNF-α含量明显高于假手术组和乌司他丁组（P〈0．05）;缺血再灌注组和乌司他丁组的IL－1β含量在6,12,24h较假手术组明显增加（P〈0．05）,但乌司他丁组增高水平明显低于缺血再灌注组（P〈0．05）;乌司他丁组在再灌注6,12,24h时bcl-2蛋白表达明显高于缺血再灌注组和假手术组（P〈0．05）．后两组各时点表达水平比较差异无统计学意义（P〉0．05）;缺血再灌注组和乌司他丁组HSP70的表达在12,24h较假手术组明显增加（P〈0．05）。病理组织学观察：乌司他丁组炎症反应较缺血再灌注组明显减轻。结论鸟司他丁能降低大鼠胰腺缺血再灌注损伤时血清TNF—α、IL-1β水平和上调胰腺组织bcl-2蛋白的表达,对大鼠胰腺缺血再灌注损伤有明显保护作用。     

乌司他丁在肝脏缺血再灌注损伤和肝脏再生中的作用

乌司他丁是一种广谱酶抑制剂,对多种脏器具有保护作用。在肝脏缺血再灌注损伤和肝再生中有无保护作用,以及其作用机制目前尚不清楚,本研究利用家兔建立肝脏缺血再灌注损伤和肝再生动物模型,观察乌司他丁对肝脏缺血再灌注损伤的保护作用,以及对残肝再生的影响,并且探讨其作用机制。     

乌司他丁对兔在体肺缺血再灌注损伤的保护作用

目的　探讨乌司他丁对活体肺缺血再灌注损伤的保护作用。方法　将 2 0只新西兰大白兔随机分成缺血再灌注损伤组 (A组 )和乌司他丁组 (B组 ) ,B组阻断前给乌司他丁 (1 0 0 0 0U/kg体重 )。两组阻断 2h和再灌注 1h后采血检测血气、白细胞介素 6(IL 6)和肿瘤坏死因子 α(TNF α)。摘取左肺测定湿干重比 (W/B)和病理学检查。结果　阻断 2h后 ,两组血氧分压 (PO2 )接近 ;恢复灌注 1h后 ,B组PO2 高于A组 (77.61± 5 .0 4 )mmHg(1mmHg =0 .1 33kPa)和 (1 0 0 .85± 6 .73)mmHg ;TNF α值 (A值 ) ,A组各时段均显著高于B组 (2 54 .0 2± 1 4 .31和 50 4 .0 2± 33 .52比 1 4 8.63± 2 1 .0 6)和 1 60 .54± 1 6 .93) ;A组肺湿干重比高于B组 ;肺外观苍白肿胀 ,病理检查见组织结构损伤。结论　乌司他丁能保护在体肺缺血再灌注中肺组织结构的损伤     

乌司他丁对失血性休克大鼠肝脏缺血再灌注损伤保护作用的研究

目的：探讨乌司他丁对失血性休克大鼠肝脏缺血再灌注损伤的保护作用及机制。方法：24只雄性Wista大鼠随机分为假手术组、生理盐水治疗组、乌司他丁治疗组,每组8只。建立大鼠失血性休克模型。乌司他丁治疗组,予以乌司他丁25000U·kg-1加入2mL生理盐水静脉推注,并完成液体复苏;生理盐水治疗组予以2mL生理盐水静脉推注,并完成复苏;假手术组,除不放血和输液外,其他处理与模型相同。观察3h后处死大鼠,取血液离心分离血浆检测肝功能指标、血清肿瘤坏死因子（TNF-α）;取肝右叶2块肝组织,1块用于肝组织病理改变和肝细胞凋亡观察;1块用于肝组织匀浆,离心取上清液进行肝组织MDA、SOD、髓过氧化物酶（MPO）检测。结果：失血性休克大鼠肝脏再灌注3h后,生理盐水治疗组肝组织发生了严重缺血再灌注损伤,肝细胞水样变,肝窦淤血变窄,间质大量炎性细胞浸润,而乌司他丁治疗组仅有轻度再灌注损伤。乌司他丁治疗组肝细胞凋亡、肝功能指标ALT、AST、血清TNF-α水平、肝组织MDA含量、MPO活性较生理盐水治疗组均有不同程度的减少（P〈0.05）,SOD活性较生理盐水治疗组升高（P〈0.05）。结论：乌司他丁对大鼠失血性休克再灌注后肝脏损伤具有保护作用,其机制可能与抑制中性粒细胞浸润、抑制氧自由基的形成、抗肝细胞凋亡相关。     

乌司他丁对下肢缺血-再灌注损伤的影响

目的观察乌司他丁对下肢缺血-再灌注期间氧自由基(OFR)代谢物丙二醛(MDA)以及促炎性细胞因子肿瘤坏死因子α(TNF-α)的影响。方法将20例单侧下肢手术病人随机分为乌司他丁组(U组,n=10)和对照组(C组,n=10)。均采用连续硬膜外麻醉。U组于上止血带前15min静脉滴注乌司他丁20万单位,松止血带前5min再次推注10万单位;C组以等量生理盐水于相同时间静脉注射。于上止血带前(T1)、松止血带后5min(T2)、15min(T3)和30min(T4)抽取术侧股静脉血,测定MDA、TNF-α浓度。结果C组在T2、T3、T4时MDA含量较T1时显著增加(P<0·01),U组仅T4时较T1时增加(P<0·05)。C组TNF-α于T3、T4时较T1时显著增高(P<0·01),U组各时点较T1时差异无显著性。结论乌司他丁对下肢缺血-再灌注损伤中OFR代谢物MDA以及促炎性细胞因子TNF-α的产生有一定抑制作用。     

肢体缺血预处理减轻肝缺血/再灌注损伤的研究进展

背景 肝缺血/再灌注损伤(hepatic ischemia/reperfusion injury,HI/RI)是肝外科手术及肝移植中常见的病理生理现象,是术后肝功能衰竭和移植物无功能的主要原因.研究表明肢体缺血预处理(limb ischemia preconditioning,LIPC)可减轻HI/RI,具体机制仍不清楚.目的 通过综述LIPC减轻HI/R1的可能机制,为临床减轻HI/RI提供新的思路.内容 介绍HI/RI机制及LIPC减轻HI/RI的可能作用机制.趋向 LIPC作为减轻HI/RI的措施具有重大的临床应用价值.     

The role of HMGB-1 on the development of necrosis during hepatic ischemia and hepatic ischemia/reperfusion injury in mice

BACKGROUND: High-mobility group 1 (HMGB-1) is a late mediator of endotoxin lethality in mice. The release of HMGB-1 is delayed compared to other proinflammatory cytokines that mediate shock and tissue injury. The purpose of this study was to investigate the role of HMGB-1 levels in response to hepatic ischemia, hepatic I/R injury, and the relationship between changes in HMGB-1 and other cytokines. MATERIALS AND METHODS: Three murine models were employed: our robust model of segmental hepatic warm ischemia (SHWI), a model of partial hepatic ischemia/reperfusion injury (PHIRI), and a model of total hepatic ischemia/reperfusion injury (THIRI). Over a 48-h period following ischemic insult and reperfusion using these models, serum HMGB-1 concentrations, concentrations of HMGB-1 in ischemic and nonischemic lobes, and serum concentrations of TNF-alpha and IL-6 levels were determined in mice. An anti-HMGB-1 antibody treatment was used in SHWI and THIRI to evaluate what aspects of response to ischemia and reperfusion were potentially mediated by HMGB-1. RESULTS: Hepatic HMGB-1 tissue concentrations exhibited biphasic changes in SHWI mice, which were increased in the ischemic lobes relative to nonischemic lobes at 12 h but decreased relative to nonischemic lobes at 24 h after ischemic insult. These results suggested that HMGB-1 was released into the systemic circulation by necrotic cells over the first 12 h but this process may be complete by 24 h postischemia. By 6 to 12 h after SHWI, serum TNF-alpha began to increase significantly and continued to increase for 18 h, followed by a sudden decline. Similarly, serum IL-6 increased over 1-3 h after SHWI and then decreased over the next 6 h. Treatment with an anti-HMGB-1 antibody significantly prolonged survival time in SHWI and THIRI. CONCLUSIONS: HMGB-1 plays a significant role in the response to hepatic ischemia and hepatic ischemia/reperfusion injury. The present study demonstrated a time-dependent production of HMGB-1 following hepatic warm ischemia in mice. The inherent HMGB-1 in ischemic areas was exhausted and HMGB-1 may be released by necrotic cells. HMGB-1 activation is involved in immediate proinflammatory stress response to I/R and anti-HMGB-1 antibody treatment remarkably improved survival. We demonstrated that systemic HMGB-1 accumulation was measured at an earlier phase of the hepatic ischemia and ischemia/reperfusion injury model than LPS-induced endotoxemia.     

肝缺血再灌注损伤与肿瘤细胞的肝内捕获及生长

肝缺血再灌注损伤（hepatic ischemia reperfusion injury,HIRI）是肝脏外科中常见的病理生理过程,是术后肝衰竭或原发性移植物无功能的重要原因。HIRI引起的黏附分子表达升高、中性粒细胞浸润、局部微循环紊乱、肝窦内皮肿胀、大量缩血管因子释放以及后期肝实质坏死、组织结构破坏及局部低氧环境可促进循环中肿瘤细胞的肝内捕获及浸润生长,本文就近年来相关研究作一综述。     

Role of leukotrienes on hepatic ischemia/reperfusion injury in rats

BACKGROUND: Leukotrienes (LT), composed of cysteinyl LT (cLT; LTC(4), LTD(4), and LTE(4)) and LTB(4), are potent lipid mediators enhancing the vascular permeability and recruitment of neutrophils, which are common features of hepatic ischemia/reperfusion (I/R) injury. The aim of this study was to investigate whether LT can mediate the liver and lung injuries following hepatic I/R. MATERIALS AND METHODS: Sprague-Dawley rats were subjected to 90 min of partial hepatic ischemia followed by 3, 12, and 24 h of reperfusion. In the hepatic and pulmonary tissues, LT content and the mRNA expression of LT-synthesis enzymes, 5-lypoxygenase (5-LO), LTC(4) synthase (LTC(4)-S), and LTA(4) hydrolase (LTA(4)-H) were measured. Tissue injuries were assessed by plasma ALT, histological examination, and wet-to-dry tissue weight ratios. RESULTS: The cLT content in the hepatic tissue after 12 and 24 h reperfusion was increased 4- to 5-fold compared to controls and this was accompanied by the enhancement of hepatic edema and plasma ALT elevation. There were no significant changes in the mRNA expression of LT-synthesis enzymes in both tissues. LTB(4) levels were not increased despite a significant neutrophil infiltration in both tissues. CONCLUSIONS: These data suggest that cLT are generated in the liver during the reperfusion period and may contribute to the development of hepatic edema and exert cytotoxicity. Factors other than LTB(4) may contribute to neutrophil infiltration.     

瘦素在肝缺血/再灌注致肾损伤中作用的研究

目的：研究瘦素（Leptin）在肝缺血/再灌注（I/R）后肾组织中的表达变化,探讨其与肝I/R介导的肾损伤的关系。方法：建立大鼠70%肝I/R模型,设立假手术和缺血60min后再灌注60、150、240、360min组,观察肾脏的病理学变化,检测各组血清尿酸、总抗氧化能力,肾Leptin蛋白及其mRNA表达的变化。结果：与假手术组比较,缺血60min/再灌注150min及再灌注240min组血清尿酸显著升高,以再灌注240min升高最为显著;再灌注240min和360min组血清总抗氧化能力显著升高,以再灌注240min升高最为显著;再灌注150、240和360min组肾Leptin蛋白表达显著升高,再灌注60、240、360min组肾LeptinmRNA表达显著升高,而再灌注150min组LeptinmRNA显著降低。病理学观察提示肝I/R早期的肾损伤较重而后期显著减轻。结论：Leptin在肝I/R后肾组织内的表达变化与肾损伤密切相关,提示它可能作为一种保护因子对抗肝I/R介导的肾损伤。     

Evaluation of a protease inhibitor in the prevention of ischemia and reperfusion injury in hepatectomy under intermittent Pringle maneuver

BACKGROUND: The severity of ischemia and reperfusion (I/R) injury is an important determinant of patient outcome in hepatic surgery. The aim of this study was to investigate the efficacy of a protease inhibitor in alleviating I/R injury to human liver in the setting of hepatectomy under intermittent Pringle maneuver. METHODS: Sixty patients who underwent liver resection under conditions of intermittent inflow occlusion were randomly assigned to 2 groups (n = 30 each) according to the use of a synthetic protease inhibitor (gabexate mesilate or GM). GM was administered intravenously at a dosage of 2.0 mg/kg/h starting 12 hours before surgery until postoperative day 2. Preoperative and intraoperative clinical variables and postoperative outcomes were evaluated. The plasma levels of a cytokine, interleukin (IL)-6, as well as laboratory biochemical liver function parameters were analyzed to evaluate hepatic I/R injury. RESULTS: The 2 groups of patients were comparable with regard to hepatic inflow occlusion time, extent of liver resection, and background liver histology. The preoperative administration of GM (GM group) substantially alleviated hepatic I/R injury compared with the untreated control group; postoperative serum transaminase levels were significantly decreased in association with marked suppression of IL-6 levels in blood circulation during surgery. This was accompanied by a lower incidence of postoperative complications. The patients without postoperative complications had significantly lower activities of plasma IL-6 at 24 hours after surgery. CONCLUSIONS: This prospective randomized study demonstrated the hepatoprotective effect of a synthetic protease inhibitor in the setting of hepatectomy under the intermittent Pringle maneuver.     

线粒体氧化应激损伤及氢气对减少肺缺血再灌注损伤作用的研究进展

肺缺血再灌注损伤(IRI)常见于肺移植,是影响肺移植术后并发症发生及受者存活的主要因素,目前临床尚缺乏缓解肺IRI的有效方法。细胞内线粒体在肺IRI过程中扮演重要角色,其主要分子机制涉及细胞内氧自由基大量积聚,进而对细胞造成一系列损伤。因此,近年来越来越多的科学家开始关注和探索如何有效降低肺IRI过程中细胞内氧自由基积聚。氢气是一种无毒、温和的选择性还原性气体,具有选择性抗氧化、抗炎和抗细胞凋亡的作用,作为一种新型抗氧化剂,其在缓解肺IRI中的作用正受到越来越多地关注。     

红景天甙对大鼠肾脏缺血再灌注损伤的保护作用

目的探讨红景天甙对大鼠肾脏缺血再灌注损伤（IRI）的预防和保护作用。方法将32只健康成年SD大鼠随机分成正常对照组、假手术组、缺血再灌注组和红景天甙组4组，每组8只。缺血再灌注组和红景天甙组分别制作肾脏缺血再灌注模型，红景天甙组予以红景天甙预处理。检测血中尿素氮（BUN）和肌酐（Scr）及肾脏中超氧化物歧化酶（SOD）、丙二酰二醛（MDA）和钠钾ATP酶（Na^＋-K^＋ATPase）含量，并用光镜和电镜观察肾脏组织形态学变化。结果红景天甙组血清BUN和Scr水平、肾皮质MDA含量较缺血再灌注组显著降低（P〈0．01），而肾皮质中SOD和Na^＋-K^＋ATPase含量与缺血再灌注组相比显著升高（P〈0．01）；肾组织光镜和电镜观察均见缺血再灌注组肾小球和肾小管上皮细胞损伤明显，而红景天甙组肾小球及肾小管仅见轻微损伤。结论红景天甙能有效降低大鼠肾脏缺血再灌注损伤（IRI），对肾脏IRI有明显的预防和保护作用，为临床上肾脏IRI提供新的预防和治疗思路。     

葛根素对家兔肝缺血再灌注一氧化氮、内皮素-1的影响

目的观察一氧化氮(NO)、内皮素-1(ET-1)在家兔肝缺血再灌注损伤过程中的变化及葛根素(Pur)对其的影响。方法实验家兔随机分为3组:对照组(C组,n=10)、缺血再灌注组(IR组,n=10)和葛根素治疗组(Pur组,n=10)。分别测定缺血前,缺血第45分钟及再灌注第45分钟时肝组织NO,ET-1含量,用电镜观察家兔HIRI及经Pur保护后的肝组织形态学改变。结果家兔缺血再灌注第45分钟时,与C组、Pur组比较:IR组血浆及组织NO含量均明显较低(P<0.01,P<0.05);IR组血浆及组织ET-1含量明显较高(P<0.01,P<0.05);与IR组比较,Pur组肝组织超微结构明显改善。结论葛根素可通过调节机体NO和ET-1水平而对肝缺血再灌注损伤发挥积极的保护作用。