Granulomatous Lung Inflammation

慢性肺部炎症的发生和维持依赖于动态 激动剂、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，这些事件有助于肉芽肿性肺部疾病的病理，包括肺生理改变、强烈的炎症和导致纤维化的受损的愈合反应。我们这一部分的总体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明确的细胞因子表型为特征的实验性肺肉芽肿的启动和维持。具体地说，我们将研究CCR4及其配体TARC/CCL17(胸腺和激活的趋化因子)和MDC/CCL22(单核细胞衍生的趋化因子)在慢性肺部炎症病理中的作用机制。我们的数据支持CCR4和it配体在肉芽肿性肺部炎症的演变过程中存在差异表达的观点，并且它们具有新的 与肉芽肿发展和纤维化相关的生物学活动。根据这些数据，我们推测TARC/MDC：CCR4在结构细胞和白细胞中的表达，通过调节细胞因子的表达、成纤维细胞的活性以及白细胞的激活和激发，是慢性肺炎症的关键成分。我们的研究将集中于以下特定目标：探讨CCR4、TARC和MDC在以1型或2型细胞因子特征为特征的慢性肺部炎症演变过程中的时程、表达幅度、细胞来源和表达机制。目的：探讨TARC、MDC和CCR4的表达通过影响细胞因子表达谱、成纤维细胞的激活以及白细胞的激活和激发来调节慢性肺炎症进展的机制。评估常驻的结构细胞来源的CCR4和TARC在维持慢性肺部炎症、通过-/-小鼠和免疫中和方面的贡献。探讨TARC/MDC-CCR4依赖的成纤维细胞与白细胞相互作用的机制，作为维持慢性炎症的重要机制。我们将研究正常小鼠和基因敲除小鼠的慢性肺部炎症模型。 免疫中和、生物检测、ELISA、Taq-Man RT-PCR和阵列分析。这项提案中设计的研究将表明CCR4及其配体在维持慢性肺部炎症方面发挥着新的作用，并将成为治疗干预的极佳靶点。

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.