MECHANISMS OF IMMUNE COMPLEX INDUCED LUNG INJURY

采用三种大鼠急性肺损伤模型（肺内注射 IgG或伊加免疫复合物沉积，或全身激活后 我们将评估L-P-，E-选择素在这些中的作用。 肺损伤模型，采用Ig-选择素嵌合体以及阻断 抗体的 其次，采用新开发的方法， ICAM-1和P-和E-选择素的测量，我们将定量 在体内评估这些粘附分子在三种细胞中的上调， 肺损伤模型。 然后我们将确定 补体和细胞因子（TNF α，IL-1）是体内 内皮粘附分子的上调。 第三，我们将 扩展了初步研究，表明IL-4的有效调节作用 和IL-10对肺内沉积的 IgG或伊加免疫复合物。 我们将评估IL-4和IL-10的作用。 10例支气管肺泡灌洗液（BAL）中TNF α、IL-1含量 和MCP-1在免疫复合物诱导的肺损伤模型中。 的 IL-4和IL-10对ICAM-1和E-受体在体内上调的影响 还将评估选择素。 同时，我们将在体外测定 IL-4和IL-10对转录上调的影响 内皮细胞ICAM-1、E-选择素、TNF α、IL-1和MCP-1以及肺泡 巨噬细胞表达后三种细胞因子。 第四，大鼠VCAM- 1将在杆状病毒系统中表达，并且抗VCAM-1抗体 将获得并在免疫复合物模型中体内使用以评估 VCAM-1的作用 第五，我们会进行体外研究， I型大鼠肺泡上皮细胞单层，以确定 β 2整合素与大鼠肺泡上皮细胞粘附相互作用的要求 巨噬细胞以及这些粘附相互作用如何影响O2的产生 和肿瘤坏死因子α。 这些研究将提供 关于粘附作用的大量额外信息 分子和细胞因子在肺损伤中的作用 最后，作为动物， 使用肺内表达的转基因小鼠， C5 a或IL-8/gro同源物KC，或使用具有C5 a或KC受体的小鼠 “敲除”，我们将确定这些操作对肺的影响 形态学和补体依赖性肺炎性反应（使用 在小鼠中，上述肺损伤模型）。

Using three models of acute lung injury in rats (following intrapulmonary deposition of IgG or IgA immune complexes, or after systemic activation of complement), we will assess the roles of L-P-,E-selectins in these models of lung injury, employing Ig-selectin chimeras as well as blocking antibodies. Secondly, employing newly developed methods for the measurements of ICAM-1, and P- and E-selectins, we will quantitatively assess in vivo the upregulation of these adhesion molecules in the three models of lung injury. We will then determine the extent to which complement and cytokines (TNFalpha, IL-1) are required for the in vivo upregulation of the endothelial adhesion molecules. Thirdly, we will extend preliminary studies that suggest potent regulatory effect of IL-4 and IL-10 on inflammatory injury following intrapulmonary deposition of IgG or IgA immune complexes. We will assess the effects of IL-4 and IL- 10 on bronchoalveolar lavage (BAL) fluids for content of TNFalpha, IL-1 and MCP-1 in the models of immune complex-induced lung injury. The effects of IL-4 and IL-10 on in vivo upregulation of ICAM-1 and E- selectin will also be assessed. In parallel, we will determine in vitro the effects of IL-4 and IL-10 on transcriptional upregulation of endothelial ICAM-1, E-selectin, TNFalpha, IL-1 and MCP-1 and alveolar macrophage expression of the latter three cytokines. Fourthly, rat VCAM- 1 will be expressed in the baculovirus system and anti-VCAM-1 antibodies will be obtained and used in vivo in the immune complex models to assess the role of VCAM-1. Fifthly, we will pursue in vitro studies with monolayers of Type I rat alveolar epithelial cells in order to determine Beta 2 integrin requirements for adhesive interactions with rat alveolar macrophages and how these adhesive interactions affect production of O2 and TNFalpha in the macrophages. These studies should provide substantial, additional information regarding the role of adhesion molecules and cytokines in lung injury. Finally, as animals are available, employing transgenic mice with intrapulmonary expression of C5a or the IL-8/gro homologue, KC, or using mice with C5a or KC receptor "knockout", we will determine the effects of these manipulations on lung morphology and on complement dependent lung inflammatory reactions (using in mice the models of lung injury referred to above).