Granulomatous Lung Inflammation

慢性肺部炎症的引发和维持取决于动力学 激发剂、炎症介质、白细胞和肺结构细胞之间的相互作用。与病因无关，这些相互作用启动了一系列慢性事件，这些事件导致肉芽肿性肺病的病理学，包括肺生理学改变、强烈炎症和导致纤维化的愈合反应受损。我们这一节的主题是确定特定趋化因子及其受体的表达和调节如何支持以确定的细胞因子表型为特征的实验性肺肉芽肿的发生和维持。具体而言，我们将研究CCR 4及其配体TARC/CCL 17（Thrombin和活化的趋化因子）和MDC/CCL 22（单核细胞衍生的化学引诱物）在慢性肺部炎症病理学中的作用机制。我们的数据支持CCR 4及其配体在肉芽肿性肺部炎症的发展过程中差异表达的概念，并且它们具有新的免疫调节作用。 与肉芽肿发展和纤维化相关的生物活性。基于这些数据，我们假设TARC/MDC：CCR 4表达，由结构细胞和白细胞，是慢性肺部炎症的关键组成部分，通过其调节细胞因子表达，成纤维细胞活性和白细胞活化和诱导的能力。我们的研究将集中在以下具体目标：调查的时间过程中，表达的幅度，细胞来源，和表达的机制CCR 4，TARC，MDC在慢性肺部炎症的演变过程中，其特征在于1型或2型细胞因子谱。确定TARC、MDC和CCR 4表达通过影响细胞因子表达谱、成纤维细胞活化和白细胞活化和诱导来调节慢性肺部炎症进展的机制作用。通过-/-小鼠和免疫中和，评估常驻结构细胞来源的CCR 4和TARC对维持慢性肺部炎症的贡献。探讨TARC/MDC-CCR 4依赖的成纤维细胞-白细胞相互作用的机制，作为慢性炎症维持的重要机制。我们将研究正常和基因敲除小鼠慢性肺部炎症的良好表征模型， 免疫中和、生物测定、ELISA、Taq-Man RT-PCR和阵列分析。本提案中设计的研究将表明，CCR 4及其配体在慢性肺部炎症的维持中发挥新的作用，并将作为治疗干预的良好靶点。

The initation and maintenance of chronic pulmonary inflammation are dependent upon dynamic interactions between an inciting agent, inflammatory mediators, leukocytes, and structural cells of the lung. Independent of the etiology these interactions set in motion a chronic cascade of events, which contribute to the pathology of granulomatous lung disease, including altered lung physiology, intense inflammation, and an impaired healing response leading to fibrosis. Our over-arching general theme of this section is to determine how the expression and regulation of specific chemokines and their receptors support the initiation and maintenance of experimental lung granulomas characterized by defined cytokine phenotypes. Specifically, we will investigate the mechanisms whereby CCR4 and its IigandsTARC/CCL17 (Thymus and activated chemokine) and MDC/CCL22 (monocyte-derived chemoattractant) contribute to the pathology of chronic lung inflammation. Our data support the concept that CCR4 and it ligands are differentially expressed during the evolution of granulomatous lung inflammation and they possesses novel biological activities associated with granuloma development and fibrosis. Based on these data, we hypothesize that TARC/MDC:CCR4 expression, by both structural cells and leukocytes, are key components of chronic lung inflammation via their ability to modulate cytokine expression, fibroblast activity and leukocyte activation and elicitation. Our studies will focus on the following Specific Aims: To investigate the time-course, magnitude of expression, cellular sources, and mechanisms of expression of CCR4, TARC, and MDC during the evolution of chronic lung inflammation characterized by a type 1 or type 2 cytokine profile. To determine the mechanistic role by which TARC, MDC, and CCR4 expression can regulate the progression of chronic lung inflammation by influencing cytokine expression profiles, fibroblast activation, and leukocyte activation and elicitation. To assess the contribution of resident, structural cell-derived CCR4 and TARC to the maintenance of chronic lung inflammation, via -/- mice and immunoneutralization. To investigate the mechanism of TARC/MDC-CCR4-dependent fibroblast-leukocyte interactions, as an important mechanism for the maintenance of chronic inflammation. We will study well characterized models of chronic lung inflammation in normal and knockout mice using immuno-neutralization, bioassays, ELISAs, Taq-Man RT-PCR, and array analyses. The studies designed in this proposal will show that CCR4 and its ligands play novel roles in the maintenance of chronic lung inflammation and will serve as excellent targets for therapeutic interventions.