Negative Regulation of Lung Inflammation by ABR/BCR

早产的人类婴儿经常发展慢性肺病（CLD），其中炎症 是一个关键的上游事件。克服和解决肺部不良反应的能力 事实上，炎症可能决定婴儿是否会继续发展CLD。的 负调节和终止炎症的机制，无论是在肺和其他地方， 我们对此知之甚少。在注射细菌内毒素LPS后，缺乏Bcr和Abr的小鼠 死于脓毒症伴肺损伤，因为他们不能下调和解决一个事件， 急性炎症这两个相关的蛋白质负调节一个小的GTbR，Rac。 缺乏A brand和B cr的巨噬细胞含有升高水平的活性Rac。有源射频激励 炎症细胞的多种功能，包括吞噬、运动和活性氧 种生产。根据我们的初步数据，我们假设Bcr和Abr呈负相关， 通过对Rac的作用调节肺部炎症。我们的研究旨在 破译时空事件（细胞类型、募集动力学、相互作用、细胞因子）， 导致缺乏Abr和Bcr的小鼠在暴露于相关的损伤后肺损伤增加， 人类CLD的发病机制，并同时寻求治疗方法来下调这一点， 过程我们建议1）确定LPS诱发的骨髓细胞动员动力学， 在没有Abr和Bcr的小鼠中细胞因子的产生2）研究促炎性嘌呤诱导的 肺泡巨噬细胞中涉及Abr和Bcr的基因表达，包括TGF-131 3）检查了 肺内皮细胞在缺乏Abr和Bcr的小鼠肺损伤中的作用4） 研究缺乏Abr和Bcr的新生小鼠是否会出现未解决的炎症和CLD 暴露于轻度高氧和LPS后5）探索慢病毒和肽策略，以终止 基于Abr、Bcr和Rac的LPS诱导的炎症。研究将使用主要 肺泡巨噬细胞、内皮细胞和无效突变小鼠。从我们的 实验将提供对存在的解决炎症的机制的深入了解， 从未被探索过。此外，还将测试肺部炎症的新疗法。因为 炎症是CLD发展的主要上游因素，我们的研究直接涉及 该计划项目的主要主题是寻求了解并最终治愈CLD。

Prematurely born human infants often develop chronic lung disease (CLD), in which inflammation is a key upstream event. The ability to overcome and resolve the adverse effects of lung inflammation may in fact determine whether an infant will go on to develop CLD or not. The mechanisms that negatively regulate and terminate inflammation, both in the lung and elsewhere, are poorly understood. Upon injection with LPS, a bacterial endotoxin, mice lacking Bcr and Abr die of sepsis with lung injury because they are unable to down regulate and resolve an episode of acute inflammation. These two related proteins negatively regulate a small GTPase, Rac. Macrophages Iacking A br a nd B cr contain elevated Ievels o f active R ac. Active R ac stimulates multiple functions of inflammatory cells including phagocytosis, motility and reactive oxygen species production. Based on our preliminary data, we hypothesize that Bcr and Abr negatively regulate inflammation in the lung through their action on Rac. Our studies are aimed at deciphering the tempo-spatial events (cell types, recruitment kinetics, interactions, cytokines) that lead to increased lung injury in mice lacking Abr and Bcr, after exposure to insults that are relevant to the pathogenesis of human CLD, and to simultaneously seek therapies to down regulate this process. We propose to 1) determine LPS-evoked kinetics of myeloid cell mobilization and cytokine production in mice without Abr and Bcr 2) investigate proinflammatory cytokine-induced gene expression involving Abr and Bcr in alveolar macrophages, including TGF-131 3) examine the role of the lung endothelium in the pulmonary injury seen in mice lacking Abr and Bcr 4) investigate if unresolved inflammation and CLD will develop in newborn mice lacking Abr and Bcr after exposure to mild hyperoxia and LPS 5) explore lentiviral and peptide strategies to terminate LPS-induced inflammation based on Abr, Bcr and Rac. Studies will be performed using primary alveolar macrophages, endothelial cells and null mutant mice. The data obtained from our experiments will provide insight into mechanisms that exist to resolve inflammation, which have never been explored. Moreover, new therapies for pulmonary inflammation will be tested. Because inflammation is a major upstream factor in the development of CLD, our studies directly relate to the Program Project's main theme of seeking to understand and ultimately cure CLD.