HEPATIC ISCHEMIA/REPERFUSION-INDUCED LUNG INJURY

高血容量性休克和复苏代表着全身性 缺血/再灌注损伤，常导致急性肺损伤 表现为成人呼吸窘迫综合征(ARDS)。尽管 导致ARDS发生的一系列复杂的炎性事件 尚未完全确定，细胞因子和中性粒细胞 被认为是肺微血管增加的影响因素 渗透性是这种综合征的特征。的Kupffer细胞 肝脏是体内最大的固定巨噬细胞群， 使肝脏具有显著的巨噬细胞依赖细胞因子的能力 制作和发行。在临床上，肝脏极易患上 低血容量休克。肿瘤坏死因子-α是一种早期反应 肝缺血/再灌流时产生的细胞因子 并在随之而来的急性肺损伤中发挥重要作用。这 肺损伤的特征是中性粒细胞大量涌入和肺组织增多。 微血管通透性。从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 在原位移植的肝脏再次移植后，可能会起到 在ARDS的发病机制中起着重要作用。我们对中性粒细胞的假设 血管再灌流后再灌流到肺的募集和外渗 肝脏缺血，导致急性肺微血管损伤为AS 如下：肝脏再灌流加速肿瘤坏死因子向肝脏的释放 静脉循环。这个系统直接排空到肺脏 微血管生成，导致肿瘤坏死因子介导的肺组织上调 ICAM-1在内皮细胞中的表达。肿瘤坏死因子同时调节局部 肺产生中性粒细胞趋化细胞因子，如ENA-78， 导致中性粒细胞趋化，在血管内激活 中性粒细胞衍生的β-2整合素的上调 黏附分子。β-2整合素与其相互作用的研究 受体/配体ICAM-1导致中性粒细胞与内皮细胞的黏附。这个 下一步导致中性粒细胞滞留和迁移到 血管间隔可能依赖于两种蛋白的持续表达 β-2整合素与中性粒细胞特异性运动(ENA-78) 趋化浓度梯度。这些事件催生了大量 中性粒细胞进入肺间质，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。此应用程序将特别指定 解决肿瘤坏死因子诱导的肺内皮细胞表达和调节 细胞ICAM-1和肺源性ENA-78，除了评估 ICAM-1和ENA-78在肝纤维化发病机制中的直接作用 缺血/再灌注性肺损伤。这项调查将 关注孤立的肝脏对肺的影响，促进 肝源性细胞因子在慢性粒细胞白血病发病机制中的作用 ARDS的发病机制及这些细胞因子在中性粒细胞中的作用 在肺中的激活和募集。

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.