Department of Medicine, University of Chicago, Chicago, Ill 60637, USA.
Transl Res. 2010 Jan;155(1):44-54. doi: 10.1016/j.trsl.2009.09.002.
Mechanical ventilation at high tidal volume (HTV) may cause pulmonary capillary leakage and acute lung inflammation culminating in ventilator-induced lung injury. Iloprost is a stable, synthetic analog of prostaglandin I(2) used to treat pulmonary hypertension, which also showed endothelium-dependent antiedemagenic effects in the models of lung injury. To test the hypothesis that iloprost may attenuate lung inflammation and lung endothelial barrier disruption caused by pathologic lung distension and coagulation system component thrombin, we used cell and animal 2-hit models of ventilator-induced lung injury. Mice received a triple injection of iloprost (2 microg/kg, intravenous instillation) at 0, 40, and 80 min after the onset of HTV mechanical ventilation (30 mL/kg, 4h), combined with the administration of a thrombin receptor-activating peptide 6 (TRAP6, 3 x 10(-7)mol/mouse, intratracheal instillation). After 4h of ventilation, bronchoalveolar lavage (BAL), histologic analysis, and measurements of Evans blue accumulation in the lung tissue were performed. The effects of iloprost on endothelial barrier dysfunction were subsequently assessed in pulmonary endothelial cells (ECs) exposed to thrombin and pathologic (18%) cyclic stretch. The combination of HTV and TRAP6 enhanced the accumulation of neutrophils in BAL fluid and lung parenchyma, as well as increased the BAL protein content and endothelial permeability judged by Evans blue extravasation in the lung tissue. These effects were markedly attenuated by iloprost. The application of 18% cyclic stretch to pulmonary ECs enhanced the thrombin-induced EC paracellular gap formation and Rho-GTPase-mediated phosphorylation of regulatory myosin light chains and myosin phosphatase. Iloprost markedly inhibited the Rho-kinase-mediated site-specific phosphorylation of myosin phosphatase, and it prevented cyclic stretch- and thrombin-induced endothelial monolayer disruption. This study characterizes for the first time the protective effects of iloprost in the in vitro and in vivo 2-hit models of VILI and supports consideration of iloprost as a new therapeutic treatment of VILI.
高容量机械通气（HTV）可能导致肺毛细血管渗漏和急性肺炎症，最终导致呼吸机引起的肺损伤。伊洛前列素是一种稳定的合成前列腺素 I（2）类似物，用于治疗肺动脉高压，它在肺损伤模型中也显示出依赖内皮的抗水肿作用。为了测试伊洛前列素可能减轻病理性肺膨胀和凝血系统成分凝血酶引起的肺炎症和肺内皮屏障破坏的假说，我们使用了呼吸机诱导的肺损伤的细胞和动物两击模型。在 HTV 机械通气（30ml/kg，4h）开始后 0、40 和 80 分钟，小鼠接受 3 次伊洛前列素（2μg/kg，静脉滴注）注射，同时给予凝血酶受体激活肽 6（TRAP6，3x10（-7）mol/只，气管内滴注）。通气 4 小时后，进行支气管肺泡灌洗（BAL）、组织学分析和肺组织中 Evans 蓝积累的测量。随后在暴露于凝血酶和病理性（18%）循环拉伸的肺内皮细胞（ECs）中评估伊洛前列素对内皮屏障功能障碍的影响。HTV 和 TRAP6 的组合增强了 BAL 液和肺实质中中性粒细胞的积累，并且增加了 BAL 蛋白含量和肺组织中 Evans 蓝外渗判断的内皮通透性。伊洛前列素明显减弱了这些作用。将 18%的循环拉伸应用于肺 ECs 增强了凝血酶诱导的 EC 旁间隙形成和调节肌球蛋白轻链和肌球蛋白磷酸酶的 Rho-GTPase 介导的磷酸化。伊洛前列素明显抑制肌球蛋白磷酸酶的 Rho 激酶介导的特异性磷酸化，并防止循环拉伸和凝血酶诱导的内皮单层破坏。本研究首次描述了伊洛前列素在体外和体内两击模型中的保护性作用，并支持将伊洛前列素作为呼吸机引起的肺损伤的新治疗方法。
