MEDIATION OF IMMMUNE COMPLEX INJURY

通过IgG免疫复合物的沉积诱导急性肺损伤，我们将 评估肺部炎症反应的四个方面： 先前未研究的粘附分子; CC趋化因子的作用;信号 涉及肺中NF κ B（和I κ B α）的转导事件， 调节性细胞因子对该信号转导过程的影响;以及， 巨噬细胞上调CD 11 c mRNA和蛋白表达的保护作用 和α（CD 11 d），在多大程度上阻断这些参与 粘附分子通过抗体影响炎症反应， 这些粘附分子的参与导致肺 损伤所有研究的终点将是白蛋白漏入肺， 支气管肺泡（BAL）中的中性粒细胞蓄积和TNF α水平 流体.关于趋化因子，我们将克隆，然后评估的作用， 大鼠CC趋化因子（MIP-1 β，MCP-1和RANTES）在肺损伤中的作用 评估肺中mRNA和蛋白质水平的变化以及 抗体诱导的这些趋化因子的阻断。这些机制 将评估趋化因子带来的影响。信号 肺炎症模型中的转导事件将集中于NF κ B 活化和NF κ B活化对TNF α的依赖性， 中性粒细胞和氧化剂。相关研究将确定 哪些调节性细胞因子（IL-6、IL-10、IL-13）抑制肺炎症 通过在体内阻断NF κ B活化（易位）来进行免疫反应。我们将 评估这些调节性细胞因子的作用是否与 保持肺内的IkappaB α水平。我们还将确定， NF κ B激活体外抑制剂抑制体内肺损伤。 最后，我们将克隆和表达大鼠组织抑制因子， 金属蛋白酶-2（TIMP-2）和分泌性白细胞蛋白酶抑制剂 （SLPI）并开发针对这些蛋白质的阻断抗体。然后我们将 检测TIMP-2、SLPI及蛋白质在肝硬化过程中的表达， 肺部炎症反应，并确定体内阻断的效果 这些抗蛋白酶。如果如预期，TIMP-2或SLPI的阻断 肺损伤加剧，其发生的机制将是 评估。本研究应明确内源性蛋白酶的作用 肺部炎症反应的抑制剂。总的来说，这些信息 将大大扩展我们对肺部炎症的理解 反应以及它是如何被触发和调节的。

Inducing acute lung injury by deposition of IgG immune complexes, we will evaluate four aspects of the lung inflammatory response: role of previously unstudied adhesion molecules; role of CC chemokines; signal transduction events involving NFkappaB (and IkappaBalpha) in lung and effects of regulatory cytokines on this signal transduction process; and, protective roles of macrophage up-regulation of mRNA and protein for CD11c and alphad (CD11d), the extent to which blocking of engagement of these adhesion molecules by antibodies affects the inflammatory response, and mechanisms by which engagement of these adhesion molecules lead to lung injury. Endpoints for all studies will be albumin leak into lung, neutrophil accumulation, and TNFalpha levels in bronchoalveolar (BAL) fluids. Regarding chemokines, we will clone and then evaluate the roles of rat CC chemokines (MIP-1beta, MCP-1 and RANTES) in lung injury by assessing changes in mRNA and protein levels in lung and effects of antibody-induced blockade of these chemokines. Mechanisms by which these chemokines bring about their effects will be evaluated. Signal transduction events in the lung inflammatory model will focus on NFkappaB activation and the dependency of NFkappaB activation on TNFalpha, neutrophils and oxidants. Related studies will determine the extent to which regulatory cytokines (IL-6, IL-10, IL-13) inhibit lung inflammatory reactions by blocking NFkappaB activation (translocation) in vivo. We will assess if the effects of these regulatory cytokines are related to preservation of IkappaBalpha levels within lung. We will also determine if in vitro inhibitors of NFkappaB activation inhibit in vivo lung injury. Finally, we will clone and express rat tissue inhibitor of metalloprotease-2 (TIMP-2) and secreted leukocyte protease inhibitor (SLPI) amd develop blocking antibodies to these proteins. We will then measure up-regulation of TIMP-2 and SLPI and protein in the course of the lung inflammatory response and determine the effects of in vivo blocking of these anti-proteases. If, as expected, blockade of TIMP-2 or SLPI intensified lung injury, the mechanism(s) by which this occurs will be evaluated. This study should define the role of endogenous protease inhibitors in lung inflammatory reactions. Collectively, this information should significantly extend our understanding of the lung inflammatory response and how it is triggered and regulated.