缺血预处理对肝脏缺血再灌注损伤中内毒素血症的影响

目的 探讨肠源性内毒素在肝脏缺血再灌注损伤中的作用以及缺血预处理对肠源性内毒素的影响。方法 将３０只ＷＥｉｓｔａｒ大鼠随机分成３组（每组１０只）,缺血再灌注组（ｉｓｃｈｅｍｉａ／ｒｅｐｅｒｆｕｓｉｏｎ,Ｉ／Ｒ）,缺血预处理组（ｉｓｃｈｅｍｉｃ ｐｒｅｃｏｎｄｉｔｉｏｎｉｎｇ,ＩＰＣ）和正常对照组。用自动生化仪测定各组丙氨酸转氨酶（ＡＬＴ０和乳酸脱氢酶（ＬＤＨ）;用鲎试剂法测定血浆内毒素;用免疫组织     

兴奋胆碱能抗炎通路对内毒素致心肌损害的保护作用

目的：研究兴奋胆碱能抗炎通路对内毒素引起大鼠心肌损害的保护作用。方法：① 内毒素休克模型[静注内毒素（LPS）10mg/kg]：设手术对照组、单纯LPS组、迷走神经切断（VC）＋LPS组和VC＋LPS＋迷走神经电刺激（VS）组,观察电刺激迷走神经对心肌组织炎症介质和心肌酶指标的影响。②内毒素血症模型（静注LPS5mg/kg）：设LPS＋电针非经非穴组、LPS＋电针足三里穴组、VC后注射LPS组和VC＋LPS＋电针足三里穴组,观察电针副交感神经相关穴位足三里穴对内毒素血症引起的心肌组织损伤的保护作用。各组大鼠均于注射LPS后2h处死,检测血浆肌酸磷酸激酶同工酶（CK-MB）活性和组织病理学改变,内毒素休克各组测定心肌组织肿瘤坏死因子-α（TNF-α）含量。结果：刺激迷走神经可明显降低内毒素休克大鼠心肌组织TNF-α含量;刺激迷走神经或电针足三里穴能显著降低LPS注射后2h大鼠血浆CK-MB活性,减轻心肌组织病理损害;切断迷走神经能显著减轻或消除电针足三里穴的作用,进一步升高血浆CK-MB活性,加重心肌组织损害。结论：刺激副交感神经激活胆碱能抗炎通路对内毒素血症和内毒素休克大鼠心脏具有不同程度的保护作用。     

肠缺血再灌注损伤后内毒素增敏作用及其机制的初步探讨

目的 探讨肠缺血再灌注损伤（Ｉ／Ｒ）对内毒素的增敏作用及其机制。方法 大鼠肠系膜上动脉阻断４５ｍｉｎ后松夹进行再灌注，静脉注射低剂量内毒素（ＬＰＳ，１．５ｍｇ／ｋｇ）。观察动物多脏器功能指标及体外诱生肿瘤坏死因子（ＴＮＦ）的改变。结果 Ｉ／Ｒ＋ＬＰＳ组显著加重全身血流动力学异常改变和肝、肺、肠等器官功能损害（Ｐ〈０．０１）。而单纯ＬＰＳ组或Ｉ／Ｒ组上述指标改变较轻或无明显异常。体外试验显示，当ＬＰ     

门静脉淤血对肠源性内毒素血症及肝脏缺血再灌注损伤的影响

目的 探讨门静脉淤血对肠源性内毒素血症及肝脏缺血再灌注损伤的影响.方法 检测家兔肝脏原位冷灌注30 min后淤血的门静脉中内毒素含量,观察清除门静脉淤血对血清内毒素、丙氨酸转氨酶(ALT)、透明质酸(HA)、肝组织匀浆丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性及肝脏组织学改变的影响.结果 门静脉阻断30 min后,每去除2.5 ml淤血可使血清内毒素含量显著下降(F=52.698,P＜0.01),但去除7.5 ml后淤血中内毒素含量不再明显下降(F=1.243,P＞0.05).去除门静脉淤血能降低复流后血清内毒素、ALT、HA和肝组织匀浆中MDA,SOD含量,改善肝脏病理学变化.其中,去除门静脉淤血在5 ml与10 ml时效果最为明显,与不去除相比较差异有统计学意义(F=4.835,P＜0.05);去除门静脉淤血2.5 ml、15 ml时与不去除相比较差异无统计学意义(F=2.275,P＞0.05).结论 首批放出的5 ml门静脉淤血中内毒素含量极高,可能是引起肝脏损伤的主要原因;放掉门静脉淤血可以减轻肠源性内毒素血症和肝脏缺血再灌注损伤.     

缺血预处理在肠缺血/再灌注损伤中的研究进展

缺血预处理是近年来提出的一种新的肠缺血/再灌注损伤的保护方法,即使在小肠长时间缺血/再灌注之前,进行一次或多次短暂的缺血,再灌注过程.研究表明缺血预处理对小肠缺血/再灌注损伤具有保护作用,但机制复杂,尚未明确.现就缺血预处理在肠缺血,再灌注损伤中的研究进展作一综述.     

肠缺血再灌注对小肠功能的影响

目的从不同角度探讨大鼠肠缺血再灌注对小肠屏障、吸收、通透和传输等功能的影响,为更深入地研究肠道损伤及其保护提供防治依据.方法以Wistar大鼠肠缺血再灌注(I/R)作模型,将动物随机分为健康对照(C)、肠系膜上动脉夹闭1h(I)、夹闭后再灌1h(R 1h)、2h(R 2h)和4h(R 4h)共5个组.分别测血或小肠组织的二胺氧化酶(DAO)、D-乳酸、D-木糖、肠传输、脂质过氧化物(MDA)和髓过氧化物酶(MPO),并作小肠普通光镜检查.结果R 1h和R 4h组的血浆DAO显著升高(P<0.05),小肠DAO各组有不同程度的降低,R 2h组降低显著,血浆和小肠DAO的变化呈负相关(r=-0.648,P<0.05).缺血和再灌注后各时相点血D-乳酸浓度升高,其中R 1h和R 2h升高显著(P<0.05).缺血再灌后肠道D-木糖的吸收增加,小肠的传输显著加快.结论肠缺血和再灌注后小肠的屏障、吸收、通透和传输功能均显示不同程度的改变.     

生长激素对肠缺血-再灌注肠粘膜屏障功能的保护作用

目的 研究生长激素对肠缺血—再灌注肠粘膜屏障的保护作用。方法 观察小肠缺血—再灌注24h小肠粘膜形态学，腹腔淋巴结细菌培养、门静脉内毒素水平、小肠粘膜细胞凋亡的改变及生长激素对其改变的影响。结果 小肠缺血—再灌注24h，小肠粘膜细胞凋亡增加，绒毛高度和数量显著降低，门静脉内毒素水平升高，腹腔淋巴结细菌培养阳性升高；生长激素能显著改善上述改变。结论 生长激素对肠缺血—再灌注肠粘膜屏障具有明显保护作用。     

预缺血对肝脏缺血再灌注损伤的保护作用

已有较多的实验证明,预缺血处理对多种缺血再灌注器官有保护作用.本文综述了预缺血对缺血再灌注肝脏的保护作用及其机理.     

川芎嗪对大鼠肠缺血再灌注肝损伤的保护作用

缺血再灌注 (I/R)损伤产生的机制主要与氧自由基大量生成导致组织器官脂质过氧化有关[1] 。本研究旨在探讨川芎嗪对大鼠肠缺血再灌注肝损伤的保护作用。一、材料与方法1.药品及试剂 :川芎嗪注射液 40mg/2ml。超氧化物歧酶 (SOD)、合胱甘肽过氧化物 (GSH) PX、丙二醛 (MDA )、Ca2 Mg2 ATPase试剂盒。2 .实验动物 :选用健康雄性Wistar大鼠 2 4只 ,体重 2 5 0 g。3 .模型制备及动物分组 :10 %水合氯醛 (0 .3 5ml/10 0 g体重 )腹腔注射麻醉后 ,仰卧固定 ,取腹部正中切口 ,暴露肠系膜上动脉 (SMA)用无损伤动脉夹夹闭其根部导致缺…     

预缺血对肝脏缺血再灌注损伤的保护作用

已有较多的实验证明,预缺血处理对多种缺血再灌注器官有保护作用.本文综述了预缺血对缺血再灌注肝脏的保护作用及其机理.     

Thymoglobulin induction protects liver allografts from ischemia/reperfusion injury

BACKGROUND: Interventions that minimize hepatic ischemia/reperfusion injury (IRI) can expand the donor organ pool. Thymoglobulin (TG) induction therapy has been shown to ameliorate delayed graft function and possibly decrease IRI in cadaver renal transplants recipients. This controlled randomized trial was designated to assess the ability of TG to protect against IRI in liver transplant recipients. PATIENTS AND METHODS: Twenty-two cadaveric liver transplant recipients were randomized to receive either TG (1.5 mg/kg/dose) during the anhepatic period and QOD x2 doses or no TG. No differences in recipients' demographics were present and donor characteristics were similar in terms of age, cause of death, and cold ischemia time. Maintenance immunosupression consisted of Tacrolimus (or Cyclosporine) and steroids for both groups. Donor biopsies were obtained during organ procurement, cold storage and 1 h after re-vascularization. Post-operative liver function tests were monitored. Early graft function, length of stay, patient and graft survival rates, incidence of primary non-function and rate of rejection were assessed. RESULTS: Patient and graft survival at 3 months was 100%. There was no incidence of primary graft non-function and no need for re-transplantation. The incidence of acute rejection was similar between the two groups. Patients in the TG group had significant decreases in alanine aminotransferase test at day 1 compared to the control group (p = 0.02). There were also near significant decreases of total bilirubin at day 5 and shorter length of hospitalization. Liver biopsy (at procurement, when cold, and post-reperfusion) of TG group demonstrated a trend for increased central ballooning. CONCLUSION: The TG allowed for more compromised liver grafts to be transplanted with less clinical evidence of IRI and improved function. Further studies on the degree of apoptosis in the liver biopsy post-reperfusion are underway.     

Akt activation protects rat liver from ischemia/reperfusion injury

BACKGROUND: Apoptosis as well as necrosis may play an important role in hepatic ischemia/reperfusion (I/R) injury. Akt, a serine-threonine protein kinase, is known to promote cell survival. We investigated whether gene transfer of constitutively active or dominant negative Akt could affect hepatic I/R injury. MATERIALS AND METHODS: Hepatic I/R injury was induced in rats by Pringle's maneuver for 20 min followed by reperfusion. Adenoviruses encoding a constitutively active form of Akt (myrAkt), a dominant negative form of Akt (dnAkt), or beta-galactosidase (LacZ) were injected through the tail vein 72 h before hepatic I/R. RESULTS: Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining demonstrated a significant increase in the positive cells 240 min after reperfusion. Immunoblotting with phospho-Akt antibody showed phosphorylation of Akt from 90 to 180 min after reperfusion. The expression of myrAkt reduced the number of TUNEL-positive cells and hepatic necrosis around the central veins in the liver after reperfusion. This expression also significantly inhibited the increase in serum alanine aminotransferase (297 +/- 131 IU/L, P < 0.05) 120 min after I/R, compared with increases in uninfected (1761 +/- 671 IU/L), LacZ adenovirus (1528 +/- 671 IU/L)-, and dnAkt adenovirus (1342 +/- 485 IU/L)-infected rats. MyrAkt expression phosphorylated Bad and inhibited the release of cytochrome-c after reperfusion. No difference in nuclear translocation of nuclear factor (NF)-kappaB, p65 was seen among the three groups of rats, however. CONCLUSION: Adenoviral gene transfer of myrAkt could inhibit apoptotic cell death and subsequent hepatic I/R injury in the rat, through Bad, not NF-kappaB.     

Heme oxygenase-1 induction by hemin protects against gut ischemia/reperfusion injury

BACKGROUND: We have shown that both intraischemic hypothermia and hypertonic saline resuscitation provide dramatic protection against gut ischemia/reperfusion (I/R) injury that is in part mediated by heme oxygenase-1 (HO-1). We therefore hypothesized that induction of HO-1 by hemin would lessen damage and improve function after gut I/R. MATERIALS AND METHODS: Male Sprague-Dawley rats were treated with 50 micromol/kg hemin (HO-1 inducer ferric protoporphyrin IX chloride) sq or vehicle 2 h before superior mesenteric artery occlusion for 60 min or sham laparotomy. After 6 h of reperfusion, transit was determined by quantitation of percentage of tracer in 10 equal segments of small intestine 30 min following injection into the duodenum (expressed as mean geometric center). Ileum was harvested for assessment of mucosal histologic injury (Chiu score 0-5 by blinded observer), myeloperoxidase activity (MPO, index of inflammation), and HO-1 protein expression. RESULTS: Hemin treatment was associated with increased HO-1 protein expression, lessened mucosal injury, decreased MPO activity, and improved intestinal transit following gut I/R. CONCLUSION: These data corroborate that HO-1 plays an important role in protecting the gut against I/R-induced injury.     

Preconditioning protects against ischemia/reperfusion injury of the liver

Ischemic preconditioning (IPC) of an organ may induce protection against the injury caused by longer duration of ischemia and subsequent reperfusion. In a standardized model of such injury in the rat liver, we used the following protocol to investigate whether adenosine played a role in IPC by preventing its enzymatic degradation by dipyridamole pretreatment according to the following protocol: group 1, non-ischemic control rats; group 2, ischemic control rats subjected to 60 minutes of ischemia by clamping of the common hepatic artery followed by 60 minutes of reperfusion; group 3, IPC with 10 minutes of ischemia followed by 15 minutes of reperfusion, prior to the ischemia/reperfusion period as in group 2; group 4, pharmacologic preconditioning with administration of dipyridamole prior to the ischemia/reperfusion period as in group 2. Peripheral liver blood flow was significantly reduced during clamping (groups 2 to 4). After unclamping, blood flow was still reduced in the ischemic rats (group 2) but had returned to preclamp values in the animals that had been subjected to ischemic (group 3) or pharmacologic (group 4) preconditioning. Liver cell injury was significantly increased in the ischemia group (group 2) only. In our experimental model of ischemia/reperfusion injury in the rat liver, we found an equally beneficial effect with ischemic and pharmacologic preconditioning. Adenosine appears to be a crucial factor in IPC.     

内毒素血症加重实验大鼠肝缺血再灌注损伤

目的探讨内毒素血症对肝缺血再灌注(I／R)损伤的影响。方法对24只大白鼠于术前1h静脉注射0．8mg／kg的LPS，检测肝门血流阻断30min的情况下复流后2h、6h、12h和24h4个时间点血清ALT与AST值，用ELISA法检测了复流后2h和6h2个时间点的循环TNF-α水平和肝组织中TNF-α含量，于复流后24h取缺血部分肝组织行组织病理学检查。24只未注射LPS的I／R肝损伤模型大鼠作为对照组。结果实验组大鼠术后各时刻ALT和AST升高幅度均明显大于对照组，并且下降缓慢；循环和肝组织中的TNF-α也明显高于对照组，复流后24h的肝组织存在片状坏死，伴大量多形核细胞浸润。结论内毒素通过升高循环和肝组织局部的TNF-α加重了缺血后再灌注肝损伤。     

心磷脂与缺血/再灌注损伤

心磷脂（CL）是维持线粒体能量代谢所必需的一种磷脂，参与了众多重要生理过程。此文对CL的结构、合成和转化；在维持线粒体正常功能中的作用；缺血／再灌注（I／R）损伤中的改变以及和线粒体功能的关系等作了逐一阐述，说明CL与I／R损伤导致的细胞死亡关系密切，CL量或性质的改变在细胞凋亡中处于中心地位。     

Kupffer细胞在肝移植缺血再灌注损伤中的双重作用

Kupffer细胞足定居于肝内的巨细胞,在月十移植缺血再灌注损伤中发挥着重要的作用,门静脉恢复血流后刺激Kupffer细胞激活,释放活性氧族、多种炎性介质和细胞因子,对肝脏造成损伤.另一方面又可上调HO-1的表达,保护肝脏缺血再灌注损伤,因此,Kupffer细胞在肝移植缺血再灌注损伤中发挥着双重效应.     

Augmenter of liver regeneration-mediated mitophagy protects against hepatic ischemia/reperfusion injury

Augmenter of liver regeneration (ALR) is an anti-apoptotic protein found mainly in mitochondria. It protects hepatocytes from ischemia-reperfusion (I/R) injury, but the underlying mechanism is not clear. We found that in rats, delivery of the ALR gene alleviated hepatic I/R injury during orthotopic liver transplantation as evidenced by reduced serum aminotransferase, oxidative stress and apoptosis, and increased expression of autophagy markers. In an in vitro hypoxia/reoxygenation (H/R) model, overexpression of the ALR gene activated autophagy and relieved defective mitophagy via the PINK1/Parkin pathway. Mechanistically, ALR transfection induced the expression of mitofusin 2 (Mfn2) in the H/R model, which led to PINK1 accumulation and mitochondrial translocation of Parkin. Deletion of Mfn2 abolished mitophagy activation induced by ALR transfection, promoted mitochondrial dysfunction, and eventually increased cell apoptosis. Mfn2 administration prevented the inhibition of mitophagy in ALR-knockout (KO) cells, thus attenuated mitochondrial dysfunction and cell apoptosis. In heterozygous ALR-knockout mice treated with a warm I/R injury, marked aggravation of liver injury was associated with mitophagy inhibition and reduction in Mfn2 expression. Taken together, our results confirm that ALR accelerated Parkin translocation and mitophagy via Mfn2, and protected hepatocytes from I/R-induced injury. Our findings provide a novel rationale for the treatment of hepatic I/R injury.     

Mycophenolate mofetil attenuates liver ischemia/reperfusion injury in rats

Mycophenolate mofetil (MMF) has been gradually introduced into clinical liver transplantation in recent years. However, the effects of MMF on hepatic ischemia/reperfusion (I/R) injury and the potential mechanisms involved are not totally understood. We aimed to evaluate whether MMF could attenuate hepatic I/R injury. MMF (20 mg/kg) or vehicle was administered to Wistar rats by gavage. The rats were then subjected to hepatic ischemia. Liver cell apoptosis and the levels of aspartate aminotransferase, myeloperoxidase (MPO), xanthine oxidase (XOD) and malondialdehyde (MDA) were determined. Expression of vascular cell adhesion molecule-1 (VCAM-1) and activation of mitogen-activated protein kinases (MAPKs) were also investigated. Furthermore, the hepatic microcirculation was observed by intravital fluorescence microscopy. Rats pretreated with MMF exhibited significant alleviation of their postischemic liver function. Liver cell apoptosis and the tissue MPO, XOD and MDA levels were decreased by MMF pretreatment. MMF also improved I/R-induced hemodynamic turbulence, as evidenced by reduced hepatic perfusion failure and decreased numbers of rolling and adherent leukocytes. I/R injury induced activation of the MAPKs pathway while expression of VCAM-1 was downregulated by MMF pretreatment. In summary, MMF attenuates hepatic I/R injury through suppression of the production of reactive oxygen species and amelioration of postischemic microcirculatory disturbances.