A treatment for lung ischemia-reperfusion injury with suppressing p38 MAP kinase

实验1FR 167653是肿瘤坏死因子（TNF）-α和白细胞介素-1（IL-1）产生的有效抑制剂，并减轻我们先前实验中的器官缺血和再灌注（I/R）损伤。由于p38丝裂原活化蛋白（MAP）激酶已被报道调节TNF-α和IL-1的产生，我们通过p38 MAP激酶的表达和激活来检测FR 167653对大鼠肺I/R模型的影响。方法：实验（Exp.）一曰：缺血1h后检测肺组织p38 MAP激酶、磷酸化p38 MAP激酶（活性型）、肺组织病理学改变及TNF-α、IL-1β的动态变化。Exp.第二章：再灌注2 h后测定动脉血氧分压（PaO_2）、动脉血氧饱和度（SaO_2）、肺组织TNF-α、IL-1β水平及肺组织病理学改变。实验1将大鼠分为三组。在对照组中，施用盐水溶液，并且在FR组中，静脉内施用0.1mg/kg/hr的FR 167653。 ...更多信息 在整个实验中，从缺血前30分钟开始。在非缺血组中，在开胸手术后不久取样。实验分为对照组和FR组。2.结果：实验1：1小时的缺血几乎没有引起肺或系列细胞因子水平的变化。同时，FR 167653显著减弱磷酸化p38 MAP激酶的表达。Exp. 2：FR组SaO_2、PaO_2较对照组明显改善，细胞因子水平降低，肺损伤减轻。结论：FR 167653通过抑制p38 MAPK的活化减轻肺I/R损伤实验2 p38 MAPK的活化在肺I/R损伤的发生、发展中起重要作用。FR 167653是一种新型p38 MAPK抑制剂。本研究评价了在犬肺移植中，使用FR 167653作为Euro-Collins溶液的添加剂，在冷缺血期间抑制p38 MAPK对随后的再灌注损伤的影响。方法：犬左肺原位移植，采用含或不含FR 167653的Euro-Collins液冷冻保存12小时后进行。再灌注15 min后结扎右肺动脉和右干支气管，再灌注后观察4 h。测定左肺血管阻力（L-PVR）、心输出量（CO）、动脉血氧分压（PaO 2）、肺泡-动脉血氧分压差（A-aDO 2）。收集肺标本进行湿/干肺重量比（WDR）测量、组织病理学研究和多形核中性粒细胞（PMN）计数。检测肺移植物中p38 MAPK活性。结果如下：FR 167653能显著改善移植后PaO 2、A-aDO_2、L-PVR、CO和WDR（p<0.05），抑制PMN浸润。FR 167653还改善了肺移植物的组织学损伤。在冷保存过程中，p38 MAPK在肺移植物中未被激活，而在再灌注30分钟后被显著激活。FR 167653在再灌注后30分钟显著抑制p38 MAPK活化（p<0.05）。结论：将FR 167653添加到Euro-Collins溶液中改善了与p38 MAPK活化抑制相关的肺移植物活力。提示抑制p38 MAPK活化可减轻肺移植缺血再灌注损伤。少

Experiment 1FR167653 is a potent suppressant of tumor necrosis factor (TNF)-α and interleukin-1 (IL-1) production, and attenuated ischemia and reperfusion (I/R) injury of organs in our previous experiment. Since p38 mitogen-activated protein (MAP) kinase has been reported to regulate the production of TNF-α and IL-1, we examined the effects of FR167653 on the rat lung I/R model by the expression and activation of p38 MAP kinase. Methods : Experiment (Exp.) 1 : After 1 hour of ischemia, p38 MAP kinase, phosphorylated p38 MAP kinase (active form), the histologic changes of the lung, and serial levels of TNF-α and IL-1β were examined. Exp. 2 : After 2 hours of reperfusion, the arterial oxygen content (PaO_2) and saturation (SaO_2), serial TNF-α and IL-1β levels, and histologic changes in the lung were examined. Rats were divided into three groups in Exp.1. In the control group, a saline solution was administered, and in the FR group, 0.1 mg/kg/hr of FR167653 was administered, intravenousl … More y throughout the experiment, beginning 30 minutes before ischemia. In the non-ischemic group, samples were taken soon after thoracotomy. The rats were divided into control and FR groups in Exp. 2. Results : Exp. 1 : One hour of ischemia induced almost no changes in the lung or serial cytokine levels. Meanwhile, FR167653 markedly attenuated the expression of phosphorylated p38 MAP kinase. Exp. 2 : SaO_2 and PaO_2 were improved, serial cytokines were lower, and lung damage was smaller in the FR group than in the control group. Conclusion : FR167653 attenuates I/R injury of the lung by suppressing the activation of p38 MAP kinase.Experiment 2The activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in the development of ischemia/reperfusion injury. FR167653 is a novel p38 MAPK inhibitor. This study evaluated the effects of p38 MAPK inhibition during cold ischemia on subsequent reperfusion injury using FR167653 as an additive to Euro-Collins solution in canine lung transplantation. Methods : Canine orthotopic left lung transplantation was performed after 12-hour cold storage using Euro-Collins solution with or without FR167653. Fifteen minutes after reperfusion, the right pulmonary artery and the right stem bronchus were ligated, and the animals were observed for 4 hours after reperfusion. Left pulmonary vascular resistance (L-PVR), cardiac output (CO), arterial oxygen pressure (PaO_2), and alveolar-arterial oxygen pressure difference (A-aDO_2) were measured. Lung specimens were harvested for wet-to-dry lung weight ratio (WDR) measurements, histopathological studies, and polymorphonuclear neutrophil (PMN) counts. The activities of p38 MAPK in lung grafts were evaluated. Results : The addition of FR167653 significantly (p<0.05) improved PaO_2, A-aDO_2, L-PVR, CO and WDR, and suppressed PMN infiltration after transplantation. FR167653 also ameliorated histological damage to the lung graft. During cold storage, p38 MAPK was not activated in the lung graft, whereas it was markedly activated 30 minutes after reperfusion. FR167653 significantly (p<0.05) inhibited p38 MAPK activation 30 minutes after reperfusion. Conclusions : The addition of FR167653 to Euro-Collins solution improved lung graft viability associated with the inhibition of p38 MAPK activation. These results suggest that inhibiting p38 MAPK activation may attenuate ischemia/reperfusion injury in lung transplantation. Less