CHEMOKINE BIOLOGY IN BRONCHIOLITIS OBLITERANS SYNDROME

（改编自申请人摘要）慢性肺移植排斥反应， 闭塞性细支气管炎综合征（BOS）是一种慢性过程， 气道的失调和异常修复的特征。 的过程 纤维增生和细胞外基质沉积， 导致气道纤维闭塞和肺功能受损。 在这 研究人员假设，持续表达的 单核细胞趋化蛋白-1（MCP-1）， 单核吞噬细胞表达CC趋化因子的募集和激活 受体2（CCR2）是一个关键的事件，促进急性连续性， 慢性肺移植排斥 具体来说，MCP-1的产生， 发生了表达CCR2的单核吞噬细胞的募集和活化 在急性排斥反应期间。 此外，MCP-1在细胞中的持续存在， 同种异体移植物维持了特定细胞群的募集和激活， 单核吞噬细胞表达CCR2。 这些细胞具有独特的亲- 促进慢性同种异体移植物纤维化的纤维化表型 拒绝BOS 了解MCP-1和CCR2之间的相互作用 从急性到慢性肺移植排斥的连续性，将导致新的 治疗和预防BOS的方法。 这项提案将检验 通过执行以下实验来验证该假设：I）确定 时间进程，表达的幅度和MCP-1的细胞来源，如 与单眼细胞表达CCR 2的募集相关， 原位大鼠肺移植急性排斥模型。 （二）确定 单核细胞趋化蛋白-1在急性肺移植发病中的作用 通过消耗MCP-1的策略进行排斥。 （三）确定时间进程 与单核细胞募集相关的MCP-1表达 CCR2在BOS小鼠模型中的表达。 B）确定具体的 利用遗传学方法研究MCP-1/CCR2生物学在BOS发病机制中的作用 用于缺失MCP-1和/或CCR 2的生物活性的方法。 第四章） 确定CCR2表达单核吞噬细胞是否表型 促纤维化（即，产生更高水平的TGF-β和PDGF），并促进 BOS发病过程中的纤维化。 通过成功完成这些 目标，申请人希望已经获得了重要的洞察力， MCP-1/CCR2生物学的持续性影响连续体和过渡 急性肺移植排斥反应的发生率 理解本 病理生物学将导致新的治疗和预防 慢性肺移植排斥反应。

(Adapted from applicant's abstract) Chronic lung allograft rejection, Bronchiolitis Obliterans Syndrome (BOS) is a chronic process that demonstrates features of dysregulated and aberrant repair of airways. This process of fibroproliferation and deposition of extracellular matrix that ultimately leads to fibro-obliteration of airways, and impaired lung function. In this proposal, the investigators hypothesize that the persistent expression of monocyte chemoattractant protein-1 (MCP-1) during an allogeneic response and recruitment and activation of mononuclear phagocytes expression CC chemokine receptor 2 (CCR2) is a pivotal event that promotes the continuum of acute to chronic lung allograft rejection. Specifically, MCP-1 production, and the recruitment and activation of CCR2 expressing mononuclear phagocytes occurs during acute rejection. Moreover, the persistent presence of MCP-1 in the allograft maintains recruitment and activation of specific populations of mononuclear phagocytes expressing CCR2. These cells have a unique pro- fibrogenic phenotype that promotes fibrogenesis of chronic allograft rejection, BOS. Understanding the interaction between MCP-1 and CCR2 during the continuum of acute to chronic lung allograft rejection, will lead to novel therapies in the treatment and prevention of BOS. This proposal ,will test this hypothesis by performing the following experiments: I) determine the time-course, magnitude of expression, and cellular sources of MCP-1, as correlated to the recruitment of monocular cells expression CCR2 in an orthotopic rat model of acute lung allograft rejection. II) determine the specific contribution of MCP-1 to the pathogenesis of acute lung allograft rejection by a strategy of depletion of MCP-1. III) determine the time-course of MCP-1 expression, as correlated to the recruitment of mononuclear cells expression CCR2 in a murine model of BOS. B) determine the specific contribution of MCP-1/CCR2 biology to the pathogenesis of BOS by using genetic approaches for deletion of the bioactivity of MCP-1 and/or CCR2. IV) determine if CCR2 expression mononuclear phagocytes are phenotypically profibrogenic (i.e., produce higher levels of TGF-beta and PDGF) and promote fibrogenesis during the pathogenesis of BOS. By successfully completing these objectives, the applicants hope to have gained significant insight into the persistence of MCP-1/CCR2 biology that impacts on the continuum and transition of acute lung allograft rejection to BOS. The understanding of this pathobiology will lead to novel therapies in the treatment and prevention of chronic lung allograft rejection, BOS.