MECHANISMS OF INFLAMMATORY LIVER INJURY

描述(改编自《调查者摘要》)：活性氧和 激活的补体因子在炎症性肝脏中的关键作用 损伤(例如，内毒素血症和缺血/再灌注)。在早期 阶段，库普弗细胞的胞外氧化应激，解毒 细胞外谷胱甘肽和大量中性粒细胞产生的活性氧 在肝脏中的定位都得到了证实。他们之前的 对ES06091支持的大鼠和小鼠的研究揭示了一个重要的 Kupffer细胞在炎症早期的作用，但它们 数据表明，中性粒细胞的涌入是关键特征。 没有它，实质细胞的损伤是最小的或没有的。因此，重点是 目前的应用是关于中性粒细胞入侵的机制 对肝脏有影响，对肝脏有毒性作用。现在人们普遍认为 黏附对于白细胞的迁移是必要的，两个实验都是如此 体外和体内研究表明，黏附可能是一个多步骤的过程。 涉及几个基因家族的成员。他们将调查粘附性 可能支持中性粒细胞在组织中定位的分子，以及 可能通过以下方式调节粘合过程的粘合分子 干扰粘连，或通过信号增强粘连和分泌 中性粒细胞的功能。他们将在小鼠身上进行这些研究 肝损伤模型，因为他们在这些方面有丰富的经验 并将在小鼠身上进行靶向删除该基因的实验 相关的黏附分子。此外，他们还将在 使用正常小鼠和黏附分子缺陷小鼠的小鼠细胞进行体外实验， 并利用人类细胞进行跨物种比较。具体目标1 将在小鼠炎症性肝损伤模型中确定 黏附分子的选择素家族在血管内皮生长中的作用 中性粒细胞在肝脏中的定位和激活。具体目标2 将在小鼠炎症性肝损伤模型中确定 β2整合素和ICAM-1在中性粒细胞定位中的作用 对肝脏和实质细胞的损伤。具体目标3将决定是否 中性粒细胞黏附促进肝细胞体外细胞毒作用 确定涉及的特定黏附分子和刺激因素 调节它们对中性粒细胞-肝细胞黏附的贡献。特定目标 4将确定可溶性ICAM-1的潜在来源和功能 炎症性肝损伤。

DESCRIPTION (Adapted from the Investigator's Abstract): Reactive oxygen and activated complement factors play critical roles in inflammatory liver injury (e.g., endotoxemia and ischemia/reperfusion). During the early phase, extracellular oxidant stress by Kupffer cells, detoxification of reactive oxygen by extracellular glutathione and massive neutrophil localization in the liver have all been demonstrated. Their previous studies of rats and mice supported by ES06091 have revealed an important contribution of Kupffer cells in the early phases of inflammation, but their data indicated that the influx of neutrophils is the critical feature without which parenchymal cell injury is minimal or absent. Thus, the focus of the current application is on the mechanisms by which neutrophils invade the liver and effect hepatotoxicity. It is now generally accepted that adhesion is necessary for leukocyte emigration, and experiments both in vitro and in vivo show that adhesion is a multistep process potentially involving members of several gene families. They will investigate adhesion molecules that potentially support neutrophil localization in tissue, and adhesion molecules that potentially modulate the adhesive process by interfering with adhesion, or by signaling enhanced adhesive and secretory functions of the neutrophil. They will perform these studies in mouse models of liver injury because they have extensive experience with these models and will perform experiments in mice with targeted deletions of the relevant adhesion molecules. In addition, they will perform studies in vitro using murine cells from normal and adhesion molecule-deficient mice, and using human cells to obtain cross-species comparisons. Specific Aim 1 will determine in mouse models of inflammatory liver injury the contributions of the selectin family of adhesion molecules to the localization and activation of neutrophils in the liver. Specific Aim 2 will determine in mouse models of inflammatory liver injury the contributions of beta2-integrins and ICAM-1 to localization of neutrophils in liver and to parenchymal cell damage. Specific Aim 3 will determine if neutrophil adhesion promotes cytotoxicity in hepatocytes in vitro and will define the specific adhesion molecules involved and the stimuli that modulate their contribution to neutrophil-hepatocyte adhesion. Specific Aim 4 will define the potential sources and function of soluble ICAM-1 in inflammatory liver injury.