T-Lymphocyte role in Lung Ischemia-Reperfusion Injury

描述（来自申请人摘要的逐字逐句）克服 缺血-再灌注损伤（I/R）是导致成功的 治疗性肺移植我们的研究计划将测试 Th 1-CD 4 + T淋巴细胞促进粒细胞介导 局部缺血后肺微血管通透性增加部分是由于 CD 4 O-CD 4 OL结合和趋化因子产生。假设将被检验 通过旨在实现以下三个具体目标的实验： I）干扰CD 4 O-CD 4 OL相互作用减弱I/R诱导的 II）白细胞介素-10（IL-10），其抑制Th 1-CD 4 + 淋巴细胞依赖性炎症反应，预防I/R诱导的肺损伤 通过调节Th 1-CD 4+淋巴细胞粘附和活化以及趋化因子 III）Th 1-CD 4+淋巴细胞/内皮细胞相互作用， 肺泡后微循环导致I/R诱导的通透性变化， 这段血管我们将测量循环淋巴细胞数量， 流式细胞术在分离大鼠和小鼠淋巴细胞亚群中的应用 接受规定时间I/R的肺。我们还将确定 通过测量离体大鼠和小鼠肺I/R引起的微血管损伤， 微血管滤过系数（Kfc）。那么Kf关于意志的变化 用于确定CD 4 O-CD 4 OL信号传导在I/R损伤中的作用 方法使用对这些分子中的每一种特异性的抗体， 使用基因工程小鼠。IL- 10的保护作用 将以类似方式检测I/R诱导的肺损伤。评估 趋化因子的产生，特别是大鼠和小鼠肺中的MIP-2， 在所有实验中。最后，我们将确定 I/R诱导的肺泡后微循环内Kfc的增加是由于 淋巴细胞介导的炎症过程，使用节段通透性 通过免疫组织化学技术， 福尔马林固定组织中CD 4 O的定位。这些研究的结果 将提供新的见解，淋巴细胞在急性I/R诱导的 肺损伤，总体目标是提高临床肺 移植程序。

DESCRIPTION (Verbatim from the applicant's abstract) Overcoming ischemia-reperfusion injury (I/R) is a critical event leading to successful therapeutic lung transplantation. Our research proposal will test the overall hypothesis that Th1-CD4+ T-lymphocytes promote granulocytic-mediated microvascular permeability increase in the post-ischemic lung in part by CD4O-CD4OL binding and chemokine generation. The hypothesis will be tested through experimentation designed to address the following three specific aims: I) Interference with CD4O-CD4OL interaction attenuates I/R-induced microvasculai injury; II) Interleukin-10 (IL-10), which inhibits Th1 -CD4+ lymphocyte-dependent inflammatoryresponses, prevents I/R-induced lung injury via modulation of Th1 -CD4+ lymphocyte adhesion and activation and chemokine production; and III) Th1-CD4+ lymphocyte/ endothelial cell interactions in the post-alveolar microcirculation result in I/R induced permeability changes to this vascular segment. We will measure circulating lymphocyte numbers and differentiate lymphocyte subsets using flow cytometry in isolated rat and mouse lungs that are subjected to defined periods of I/R. We will also determine microvascular damage due to I/R in isolated rat and mouse lungs by measuring the microvascular filtration coefficient (Kfc). Changes in Kf about will then be used to determine the contribution of CD4O-CD4OL signaling in the I/R injury process using antibodies specific to each of these molecule' and through the use of genetically engineered mice. The protective effects of IL- 10 against I/R-induced lung damage will be tested in a similar manner. Assessment of chemokine production, specifically MIP-2 in the rat and mouse lung, will be performed in all experiments. Finally, we will determine whether the I/R-induced increase in Kfc within the post-alveolar microcirculation is due to lymphocytic-mediated inflammatory processes, using segmental permeability measures and by employing immunohistochemistry techniques for identifying the localization of CD4O in formalin-fixed tissues. The results of these studies will provide novel insight as to the role of lymphocytes in acute I/R-induced lung damage with the overall goal of improving success rates for clinical lung transplantation procedures.