The effects of intraportal prostaglandin E1 administration on hepatic warm ischemia and reperfusion injury in dogs

To determine the route of prostaglandin E₁ (PGE₁) administration which would have the greatest protective effect against hepatic warm ischemia, two experiments were performed using dogs. The pharmacokinetics of PGE₁ were investigated in a preliminary study, after which, the effects of PGE₁ in a 90-min warm ischemic liver model were examined. The dogs were divided into three groups of ten, according to the treatment given: group A was an untreated control group, group B received PGE₁ intravenously, and group C received PGE₁ intraportally. The PGE₁ was infused continuously at a rate of 0.02 g/kg/min before and after ischemia. All the dogs in groups A and B died within 24 h of induced ischemia. Whereas, six of the ten dogs in group C survived for over 3 days. The arterial ketone body ratio was not maintained in groups A and B, but it was in group C. Furthermore, in group C the serum lipid peroxide level, which reflects hepatocellular membrane damage, was maintained at a lower level than that in the other groups after ischemia. Electron microscopy revealed sinusoid destruction and changes in both the plasma membrane and parenchymal cell mitochondria in groups A and B, while in group C these structures were well preserved. These findings confirmed that intraportally administered PGE₁ improved the hepatic microcirculation and stabilized the hepatocellular membranes. Our results indicate that intraportal administration of PGE₁ has a greater protective effect than intravenous administration against warm ischemic liver injury.     

The mechanism of hepatic graft protection against reperfusion injury by prostaglandin E1

1 (PGE₁) on protecting against hepatic endothelial cell damage and increasing graft viability after cold preservation and reperfusion, using an isolated perfused rat liver (IPRL) model. The grafts were divided into three groups, according to the cold preservation time and PGE₁ administration, namely: 4 h preservation (group 1, n = 9), 6 h preservation (group 2, n = 9), and 6 h preservation followed by PGE₁ infusion (group 3, n = 9). After cold storage, the grafts were put on the recirculating IPRL system, then reperfused for 120 min at 37°C with oxygenated Krebs-Henseleit buffer containing hyaluronic acid (HA). To examine the function of the sinusoidal endothelial cells and hepatocytes, serial measurements of HA, tumor necrosis factor-α (TNFα), thromboxane B₂ (TXB₂), acid phosphatase, and conventional parameters in the perfusate were made. After perfusion, the trypan blue exclusion test was performed to assess the presence of any microscopic sinusoidal lining cell damage. In group 3, the bile output and HA clearance were significantly greater, while glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, TNFα, TXB₂, and acid phosphatase in the perfusate were significantly lower than in group 2. Histologically, less endothelial cell damage and hepatocyte damage than in group 2 was also confirmed. These results therefore suggest that the improvement of hepatic graft viability by PGE₁ administration is mainly due to sinusoidal endothelial cell protection. (Received for publication on Nov. 21, 1996; accepted on Nov. 6, 1998)     

Effects of remifentanil on neutrophil adhesion, transmigration, and intercellular adhesion molecule expression

BACKGROUND: Anaesthetic drugs are used for pain therapy and anaesthesia. Neutrophils play a significant role during the process of inflammation. The aim of the current study was to investigate the effects of remifentanil and fentanyl on neutrophil migration through endothelial cell monolayers, and on adhesion molecule expression. METHODS: After isolation of polymorphonuclear neutrophils (PMNL) we used a currently described migration assay. PMNL and/or endothelial cell monolayers (ECM) were pre-treated with remifentanil using clinically relevant, as well as higher and lower concentrations or relevant concentrations of fentanyl. RESULTS: Concentrations of remifentanil (50 ng/mL) similar to the relevant plasma concentration were able to inhibit PMNL migration through ECM significantly (migration compared to the control 82+/-7% SD; P<0.05), when both cell types were treated with the synthetic narcotic remifentanil. Fentanyl (30 ng/mL) showed a stronger inhibitory effect (migration compared to the control 67+/-9.2%; P<0.05). Endothelial cell adhesion molecule expression was reduced after either remifentanil or fentanyl. CONCLUSION: The results of the present investigation indicate that remifentanil influences interaction of ECM against human neutrophils. Compared to fentanyl, remifentanil seems to exhibit minor inhibitory effects on neutrophil migration.     

细胞间黏附分子-1单克隆抗体对全脑缺血再灌注损伤大鼠的脑保护作用

目的 评价细胞间黏附分子-1单克隆抗体(1A29)对全脑缺血再灌注损伤大鼠的脑保护作用.方法 健康成年雄性SD大鼠40只,体重180～200 g,2～3月龄,采用四血管法制备全脑缺血再灌注模型.随机分为4组(n=10):Ⅰ组于缺血前即刻股静脉注射同型对照抗体1 mg/kg;Ⅱ组～Ⅳ组分别于缺血前即刻、再灌注即刻及再灌注4 h时股静脉注射1A29 1 mg/kg.于再灌注24 h时进行神经功能损伤评分、脑组织多形核白细胞及单核细胞计数,并计算脑梗死面积百分比及脑组织含水量.结果 与Ⅰ组比较,其余3组脑组织多形核白细胞计数、单核细胞计数、脑梗死面积百分比、含水量及神经功能损伤评分均明显降低(P<0.01),3组间差异无统计学意义(P>0.05).结论 缺血前或再灌注4 h内静脉注射1A29均可减轻大鼠全脑缺血再灌注损伤.     

Experimental study of the effect of intraportal prostaglandin E1 on hepatic blood flow during reperfusion after ischaemia and hepatectomy.

BACKGROUND: Prostaglandin E1 (PGE1) has protective effects experimentally and clinically in individual models of hepatic ischaemia-reperfusion injury and of partial hepatectomy. The present study investigated the effects of intraportal administration of PGE1 on hepatic blood flow, systemic arterial pressure and long-term animal survival after 60 min of total liver ischaemia followed by 70 per cent partial hepatectomy in rats. METHODS: Total liver ischaemia was induced by occluding the hepatoduodenal ligament for 60 min. PGE1 0.5 microg per kg per min was infused intraportally for 15 min before inducing ischaemia and for 120 min after ischaemia in the treatment group. Normal saline was infused in the control group. During ischaemia 70 per cent partial hepatectomy was performed. Portal venous flow (PVF), peripheral tissue blood flow (PTBF) and hepatic artery flow were measured before and after ischaemia. Serum biochemical analysis was carried out at 1, 3 and 24 h, and 7 and 14 days; and liver histology at 1 and 24 h, and 7 days after reperfusion. Survival was followed for 1 year. RESULTS: Intraportal infusion of PGE1 significantly improved PVF and PTBF without affecting the systemic arterial pressure. Long-term survival was significantly higher in the PGE1 group. Serum aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase levels decreased significantly, and 2-h bile flow was significantly improved, in the PGE1 group. Histological examination revealed significant portal venous congestion, sinusoidal congestion, fatty degeneration and tissue necrosis 24 h and 7 days after reperfusion in the control group. CONCLUSION: PGE1 has a protective effect against liver damage when the liver is injured by warm ischaemia and reperfusion followed by partial resection.     

缺血再灌注对大鼠肺细胞间粘附分子-1表达的影响

目的 观察缺血再灌注（Ｉ／Ｒ）对肺组织细胞间粘附分子－１（ＩＣＡＭ－１）表达的影响，分析ＩＣＡＭ－１表达与肺内中性粒细胞浸润的关系。方法 Ｗｉｓｔａｒ大鼠单肺原位热缺血再灌注损伤模型分７组，左肺缺血９０ｍｉｎ，再灌注时间分别为０、１、２、４、８、１６、２４ｈ。逆转录－聚合酶链式反应（ＲＴ－ＰＣＲ）法及Ｗｅｓｔｅｒｎ ｂｌｏｔ法检测肺组织ＩＣＡＭ－１ｍＲＮＡ及蛋白表达，测定各组肺组织髓过氧化物酶活性     

Role of P-selectin expression in hepatic ischemia and reperfusion injury

Background. Researchers have shown that reperfusion of ischemic tissues initiates a complex series of reactions that paradoxically injure tissues. Although several mechanisms have been proposed to explain the pathobiology of ischemic/reperfusion (I/R) injury, much attention has focused on adhesion molecules. Our research is intended to show the kinetics of P-selectin in the liver in response to I/R injury.Methods. Left-lobar hepatic ischemia was induced for 30 min in 35 C57BL-6 mice and 20 P-selectin-deficient (K-O) mice. P-selectin expression was measured in these mice at 20 min, 2, 5, 12 and 24 h reperfusion times, as well as in control and sham animals. The animals were injected with radio-labeled P-selectin monoclonal antibody and the organs were harvested for counts/g tissue, expressed as the percentage injected dose. Serum liver enzymes were measured and pathological sections of ischemic and control livers were performed. The unpaired t -test was used for statistical analysis.Results. P-selectin expression showed two peaks in this animal model. The first peak was at 20 min and the second peak at 5 h of reperfusion (p<0.001). We documented an 8-fold increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels 10 h following I/R injury. Pathological specimens showed periportal necrosis consistent with an ischemic event. P-selectin K-O mice showed no up-regulation as a separate control group, and the liver enzymes were significantly lower than the wild-type mice at 10 h (p<0.001).Conclusion. P-selectin has a bimodal expression following hepatic I/R injury. The first peak is attributed to the Weibel–Palade bodies and the second to new translational P-selectin. We noted no difference in the up-regulation of P-selectin in the ischemic and non-ischemic liver lobes in the same animal.     

1-磷酸鞘氨醇与肺缺血/再灌注损伤

背景1-磷酸鞘氨醇(sphingosine-1 -phosphate,S1P)是鞘脂的代谢产物,不仅与细胞表面特定受体(S1PR1-5)结合产生多种生物学效应,还作为细胞内第二信使发挥作用。S1P在细胞增殖、移动、凋亡及心血管系统、免疫系统等方面都有重要的调节作用,因而参与到生物体内许多生理和病理过程。目的现就近年来的...     

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.     

雾化吸入前列腺素E1对家猪单肺通气期间分流及氧合的影响

随着心胸外科的发展、各种微创手术的推广,单肺通气(OLV)得到了广泛的应用。但是OLV时流经无通气肺的血液没有得到氧合回到左心,会造成静脉血掺杂、动脉血氧分压(PaO2)降低。虽然低氧性肺血管收缩效应(HPV)可使非通气肺血流减少并转向通气肺,减少了肺内分流,但仍有约9%~27%的病人可发生显著低氧血症[1]。而且HPV使肺血管阻力(PVR)显著增高,右心后负荷增大,可引发心脏病、低血容量以及肺动脉高压患者心脏功能急剧恶化。因此,寻找既能降低分流改善氧合又能降低PVR、减小心脏负荷的方法对于OLV今后更广泛的应用具有重要意义。由于通…     

脂质体携前列腺素E1对皮瓣缺血—再灌注损伤的保护作用

目的探讨脂质体携载前列腺素E     

氨溴索对大鼠肝脏缺血再灌注损伤的保护作用

目的：探讨氨溴索对大鼠肝脏缺血再灌注损伤（I/RI）的保护作用及其机制。方法：18只雄性Wistar大鼠被随机均分为假手术组、肝I/RI模型组（模型组）、氨溴索预处理+肝I/RI模型组（氨溴索预处理组）。肝I/RI模型采用阻断入肝血流30 min后再灌注方法诱导,氨溴索预处理组于缺血前20 min尾静脉注射氨溴索（100 mg/kg）,而模型组给予等体积生理盐水。术后6 h处死大鼠,检测血清丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平和肝组织病理学改变,同时检测肝组织超氧化物岐化酶（SOD）,谷胱甘肽（GSH）,丙二醛（MDA）含量,caspase-3的活化水平。结果：与假手术组比较,模型组与氨溴索预处理组血清ALT和AST水平明显升高（均P<0.05）;肝组织出现明显的病理学改变;肝组织SOD和GSH含量明显下降,而MDA水平明显升高（均P<0.05）;肝组织caspase-3活化水平明显升高（均P<0.05）。与模型组比较,氨溴索预处理组以上各项指标的变化均明显减弱（均P<0.05）。结论：氨溴索预处理能减轻大鼠肝脏I/RI,机制可能与其调控抗氧化和抗凋亡信号通路有关。     

The effect of a nitric oxide donor on endogenous endothelin-1 expression in renal ischemia/reperfusion injury

The balance between nitric oxide (NO) and endothelin-1 (ET-1) production is essential to the vascular function that controls organ perfusion. Elevated ET-1 levels in the peritubular capillary network following renal transplantation may be associated with renal allograft rejection. Administration of a nitric oxide donor during the preischemic period has been shown to protect kidney against ischemia-reperfusion injury, but the mechanism underlying this therapeutic benefit remains incompletely understood. We hypothesized that early administration of the NO donor sodium nitroprusside (SNP) may suppress ET-1, thereby improving renal function in an ischemia/reperfusion injury. Sprague-Dawley rats were subjected to 60 minutes of renal warm ischemia and contralateral nephrectomy. Renal biopsies were performed prior to ischemia and reperfusion, and at 1 hour and 48 hours after reperfusion. The animals were divided into four groups: sham group without warm ischemia; early SNP group (SNP given before ischemia); late SNP group (SNP given before reperfusion); and ischemic control. ET-1 expression was assessed by semiquantitative analysis with immunohistochemical stain using ET-1 monoclonal antibody and hematoxylin-eosin staining. Serum creatinine was measured at 48 hours after reperfusion. There were significant improvements in all parameters of the early compared with the late SNP group and the ischemic control, but there was no difference between the late SNP group and the ischemic control. These data suggest that early administration of SNP in renal ischemia-reperfusion improves renal function by suppressing ET-1 expression.     

脂质体携前列腺素E_1对皮瓣缺血-再灌注损伤的保护作用

目的　探讨脂质体携载前列腺素E1 (PGE1 )对大鼠皮瓣缺血 再灌注损伤的保护机制。方法　制成大鼠下腹部岛状皮瓣缺血 再灌注损伤模型 ,将 32只大鼠随机分为 4组 ,用测量、称重以及组织化学、放射免疫和原子吸光度的方法进行观察。结果　脂质体携载PGE1 治疗明显减轻缺血 再灌组织及细胞线粒体的钙超载 (P <0 .0 1) ,抑制缺血 再灌注引起的血浆乳酸脱氢酶和组织蛋白酶D活性增加 (P <0 .0 1) ,降低血浆脂过氧化物丙二醛含量和血浆内皮素含量 (P <0 .0 5 )。脂质体携载PGE1 的治疗作用明显优于相同剂量的游离PGE1 的作用。结论　脂质体携载PGE1 对皮瓣缺血 再灌注损伤具有潜在临床治疗价值。     

Heparin-binding EGF-like growth factor downregulates expression of adhesion molecules and infiltration of inflammatory cells after intestinal ischemia/reperfusion injury

Background/Purpose: This study examined whether heparin-binding epidermal growth factor (EGF) like growth factor (HB-EGF), a proven intestinal cytoprotective molecule, exerts its protective effects through modulation of adhesion molecule expression and inflammatory cell infiltration, important pathogenic mediators of ischemia/reperfusion (I/R) injury. Methods: Total midgut I/R injury in rats was achieved by occlusion of the superior mesenteric artery for 90 minutes followed by reperfusion. Rats were treated intraluminally with 600 [mu ]g/kg HB-EGF or with PBS 45 minutes after the onset of ischemia. Four- or 24-hours post-I/R, ileum was harvested and processed for immunhistochemical detection of P-/E-selectins, intercellular adhesion molecule[ndash ]1 (ICAM-1)/vascular cell adhesion molecule[ndash ]1 (VCAM[ndash ]1), and polymorphonuclear cells (PMN)/macrophages (M[Phi ]). Results: P-/E-selectins were significantly induced in vascular endothelia 4 hours after I/R injury compared with normal intestine. HB-EGF treatment significantly down-regulated the expression of P-/E-selectins. I/R-injured intestine displayed overexpression of ICAM-1 and VCAM-1, which were significantly down-regulated by HB-EGF treatment. Lastly, I/R injury caused significant infiltration of PMN and M[Phi ] into wounded tissue 24 hours after I/R compared with normal intestine. HB-EGF treatment significantly decreased PMN and M[Phi ] infiltration into the injured tissue. Conclusions: HB-EGF intestinal cytoprotection is mediated, in part, by down-regulation of expression of adhesion molecules and infiltration of PMN and M[Phi ] after intestinal I/R injury. J Pediatr Surg 38:434-439.     

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.