Pulmonary Alveolar Macrophage Function in Humans

人类肺泡巨噬细胞的功能

基本信息

批准号：
7273672
负责人：
Alan D Schreiber
金额：
$ 43.84万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1981
资助国家：
美国
起止时间：
1981-04-01 至 2009-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Macrophages present in the lung parenchyma and within the airway lumen are critical components of immune complex mediated acute lung injury. Following exposure to immune complexes, macrophages accumulate in the lung and induce the release of cytokines and other biologically active products. These responses are largely initiated by Fcgamma receptors (FcgammaR) on the macrophage surface that interact with IgG containing complexes. Syk kinase plays a critical role in the signaling machinery of FcgammaRs and our studies have demonstrated that targeted disruption of Syk in the lung leads to inhibition of FcgammaR function and thereby to a salutary impact on immune complex induced pulmonary inflammation. Our studies will combine in vitro and in vivo molecular and cell biology approaches to further examine how Syk contributes to IgG mediated lung injury. In as much as Cbl, through its function as a ubiquitin ligase, promotes degradation negative regulation of Syk and modulates the function of a number of receptors, our thesis is that by promoting Syk and/or FcgammaR ubiquitination, Cbl in alveolar macrophages (AM) inhibits the release of inflammatory mediators. For in vivo studies of the effect of Cbl on immune complex mediated lung inflammation, we will utilize Cbl knockout (KO) mice and our unique Cbl KO mice transgenic (TG) for human FcgammaRIIA in an established mouse model of immune complex mediated lung injury. For ex vivo studies, we will determine Fc(R induced mediator re-lease from the AM of these mice. Another aim is based on the relationship of Syk to FcgammaR function and our unexpected observation that PECAM-1 enhances lung FcgammaR mediated PMN influx, TNF release and phagocytosis. This aim will examine the interaction of PECAM-1 with FcgammaR/Syk in AM. We have available PECAM-1 140 mice and have created PECAM-1 KO mice TG for FcgammaRIIA. In addition, since epithelial cells are considered important in inflammatory disorders, we will build on our observation that bronchial epithelial cells express Syk kinase and explore the role of Syk in the release of inflammatory mediators by lung epithelial cells. Finally, in extension of our novel observation that FcgammaR mediated phagolysosomal fusion (affected by Syk kinase) and its associated calcium signal requires a FcgammaR cytoplasmic sequence distinct from that required for the initial internalization step of phagocytosis, we will examine parameters of phagolysosomal fusion by FcgammaR. Continued progress in understanding the interactions of Fc(Rs and Syk kinase is important for development of new approaches in the treatment of inflammatory/immune complex disorders of the lung.

描述（由申请人提供）：肺实质和气道管腔内存在的巨噬细胞是免疫复合物介导的急性肺损伤的关键成分。暴露于免疫复合物后，巨噬细胞积聚在肺中，并诱导细胞因子和其他生物活性产物的释放。这些反应在很大程度上是由fcgamma受体（FCGAMMAR）在巨噬细胞表面与含有IgG相互作用的复合物相互作用的。 SYK激酶在FCGAMMARS的信号机制中起关键作用，我们的研究表明，靶向Syk在肺中的靶向破坏会导致抑制FCGAMMAR功能，从而对免疫复合物诱导的肺部炎症产生有益的影响。我们的研究将结合体外和体内分子和细胞生物学方法，以进一步研究SYK如何促进IgG介导的肺损伤。在CBL中，通过其作为泛素连接酶的功能，促进SYK的降解负调控并调节许多受体的功能，我们的论点是，通过促进SYK和/或FCGAMMAR泛素化，肺泡巨噬细胞中的CBL（AM）在肺泡巨噬细胞（AM）中抑制了炎症剂的释放。为了在体内研究CBL对免疫复合物介导的肺部炎症的影响，我们将利用CBL敲除（KO）小鼠和我们独特的CBL KO小鼠转基因（TG）对人fcgammariia中的人体FCGammariia中的既定小鼠模型的免疫复合物介导肺损伤。对于离体研究，我们将确定FC（R诱导的这些小鼠的AM租赁。另一个目的是基于SYK与FCAMMAR功能的关系以及我们意外的观察到PECAM-1增强肺FCMAMAR介导的PMN Imprux，TNF，TNF，TNF释放和吞噬细胞的关系。该目标将检查Pecam-1的相互作用。小鼠并为FCGammariiA创建了PECAM-1 KO小鼠，因为上皮细胞在炎症性疾病中被认为很重要，我们将基于我们的观察结果，即支气管上皮细胞表达SYK激酶，并探索SYK在SYK释放中的作用。吞噬肿瘤融合（受SYK激酶的影响）及其相关的钙信号需要fcmamar的细胞质序列，与吞噬作用的初始内在化步骤所需的fc玛氏序列，我们将检查FCGAMMAR的吞噬性溶血体融合的参数。在理解FC的相互作用方面的持续进展（RS和SYK激酶对于开发肺部炎症/免疫复杂疾病的新方法很重要。