HEPATIC ISCHEMIA/REPERFUSION-INDUCED LUNG INJURY

高血容量性休克后复苏代表全身性 缺血/再灌注损伤，并经常导致急性肺损伤 表现为成人呼吸窘迫综合征（ARDS）。虽然 导致ARDS发展的一系列复杂炎症事件 尚未完全确定，细胞因子和中性粒细胞已被 作为肺微血管增加的效应物， 渗透性是这种综合征的特征。Kupffer细胞的 肝脏代表体内最大的固定巨噬细胞群， 给予肝脏巨噬细胞依赖性细胞因子的显著能力 生产和发布。在临床上，肝脏非常容易受到 低血容量性休克肿瘤坏死因子-α（TNF）是一种早期反应， 在肝缺血/再灌注背景下产生的细胞因子 损伤，并在随后的急性肺损伤中起重要作用。这 肺损伤的特征在于中性粒细胞流入和肺内分泌增加。 微血管通透性肝脏释放的细胞因子 低血容量性休克和复苏（缺血/再灌注损伤），或 在原位移植的肝脏重新植入后， 在ARDS发病机制中的作用。我们对中性粒细胞的假设 再灌注后， 缺血性肝脏，导致急性肺微血管损伤， 如下：肝再灌注促使TNF释放到肝中 静脉循环这个系统直接排入肺部 微血管，导致TNF介导的肺微血管 内皮细胞ICAM-1的表达。TNF同时介导局部 肺产生中性粒细胞趋化性细胞因子，如ENA-78， 导致嗜中性粒细胞趋化性，血管内激活 隔室，以及嗜中性粒细胞衍生的β-2整联蛋白的上调 粘附分子β-2整合素与其受体的相互作用 受体/配体，ICAM-1，导致嗜中性粒细胞-内皮细胞粘附。的 接下来的步骤导致中性粒细胞渗出和迁移超过 血管隔室可能依赖于持续表达 β-2整合素和沿着嗜中性粒细胞特异性（ENA-78）的运动 趋化性浓度梯度这些事件促使 中性粒细胞进入肺动脉内膜，导致中性粒细胞- 介导的肺损伤，表现为微血管通透性增加， 组织损伤和器官功能障碍该应用程序将具体 探讨TNF诱导的肺内皮细胞表达及调控 细胞ICAM-1和肺源性ENA-78，除了评估 ICAM-1和ENA-78在肝硬化发病机制中的直接作用 缺血/再灌注诱导的肺损伤。这次调查将 关注孤立肝脏对肺的影响， 肝源性细胞因子在肝硬化中的机制作用的评价 急性呼吸窘迫综合征的发病机制及这些细胞因子在中性粒细胞 激活并募集到肺中。

Hypervolemic shock followed by resuscitation represents a systemic ischemia/reperfusion injury, and often leads to acute lung injury manifested as the Adult Respiratory Distress Syndrome (ARDS). Although the complex series of inflammatory events that lead to the development of ARDS have not been completely determined, cytokines and neutrophils have been implicated as effectors of the increase in pulmonary microvascular permeability that characterizes this syndrome. The Kupffer cells of the liver represent the largest fixed macrophage population in the body, giving the liver a significant capacity for macrophage-dependent cytokine production and release. Clinically, the liver is highly susceptible to hypovolemic shock. Tumor necrosis factor-alpha (TNF) is an early response cytokine that is produced in the context of hepatic ischemia/reperfusion injury and plays a significant role in the ensuing acute lung injury. This lung injury is characterized by neutrophil influx and increased pulmonary microvascular permeability. Cytokines released from the liver during hypovolemic shock and resuscitation (ischemia/reperfusion injury), or following reimplantation of an orthotopically transplanted liver, may play a role in the pathogenesis of ARDS. Our hypothesis for neutrophil recruitment and extravasation into the lung following reperfusion of an ischemic liver, with resultant acute pulmonary microvascular injury is as follows: hepatic reperfusion precipitates TNF release into the hepatic venous circulation. This system empties directly into the pulmonary microvasculature, causing TNF-mediated upregulation of pulmonary endothelial expression of ICAM-1. TNF concurrently mediates the local pulmonary generation of neutrophil chemotactic cytokines, such as ENA-78, resulting in neutrophil chemotaxis, activation within the intravascular compartment, and upregulation of neutrophil-derived beta-2 integrin adhesion molecules. The subsequent interaction of beta-2 integrin with its receptor/ligand, ICAM-1, results in neutrophil-endothelial adhesion. The next steps leading to neutrophil diapedesis and migration beyond the vascular compartment may be dependent upon both continued expression of beta-2 integrins and movement along a neutrophil-specific (ENA-78) chemotactic concentration gradient. These events precipitate an influx of neutrophils into the pulmonary interstitium, resulting in neutrophil- mediated lung injury, manifested as increased microvascular permeability, tissue injury, and organ dysfunction. This application will specifically address TNF-induced expression and regulation of pulmonary endothelial cell ICAM-1 and pulmonary-derived ENA-78, in addition to assessing the direct effects of ICAM-1 and ENA-78, in the pathogenesis of hepatic ischemia/reperfusion-induced pulmonary injury. This investigation will focus on the impact of an isolated liver in on the lung, facilitating evaluation of the mechanistic role of hepatic-derived cytokines in the pathogenesis of ARDS and the role that these cytokines play in neutrophil activation and recruitment in to the lung.