MECHANISMS OF INFLAMMATORY LIVER INJURY

描述（改编自研究者摘要）：活性氧和 激活的补体因子在炎症性肝脏中起关键作用 损伤（例如，内毒素血症和缺血/再灌注）。 早期 期，枯否细胞的细胞外氧化应激， 活性氧通过细胞外谷胱甘肽和大量中性粒细胞 在肝脏中的定位均已得到证实。 他们以前 由ES 06091支持的大鼠和小鼠研究揭示了一个重要的 库普弗细胞在炎症早期的贡献，但他们的 数据表明，中性粒细胞的流入是关键特征 没有这些细胞，实质细胞损伤是最小的或不存在。 因此，重点 目前的应用是中性粒细胞入侵的机制， 肝和影响肝毒性。 现在人们普遍认为， 粘附是白细胞迁移所必需的， 体外和体内研究表明，粘附是一个多步骤的过程， 涉及多个基因家族的成员。 他们将研究粘附性 可能支持中性粒细胞在组织中定位的分子，以及 粘附分子通过以下方式潜在地调节粘附过程 干扰粘附，或通过信号增强粘附和分泌 中性粒细胞的功能。 他们将在小鼠中进行这些研究 肝损伤模型，因为他们有丰富的经验， 模型，并将在小鼠中进行实验，靶向删除 相关粘附分子。 此外，他们还将在以下方面进行研究： 体外使用来自正常和粘附分子缺陷小鼠的鼠细胞， 并使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 选择素家族的粘附分子的贡献， 中性粒细胞在肝脏中的定位和活化。 具体目标2 将在小鼠炎症性肝损伤模型中确定 β 2-整合素和ICAM-1对中性粒细胞定位的作用 肝脏和实质细胞损伤。 具体目标3将确定是否 中性粒细胞粘附促进体外肝细胞的细胞毒性， 定义了所涉及的特定粘附分子和刺激， 调节它们对嗜中性粒细胞-肝细胞粘附的贡献。 具体目标 4将明确可溶性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.