Th2 cytokines and CC chemokines in pulmonary fibrosis

特发性肺纤维化的发病机制是 以伴随着强烈的炎症反应为特征的 纤维增生和细胞外基质沉积。首字母 炎性细胞募集的刺激及其机制 慢性炎症、肉芽组织的持续和演变 其形成、形成和纤维化的机制尚未完全阐明。而IL-13，一种Th2 细胞因子，已被证明对成纤维细胞有直接影响， 它也是一种新的CC趋化因子CIO的有效诱导剂， 对单核巨噬细胞有趋化作用。巨噬细胞/单核细胞 吞噬细胞已被证明在该病的发病机制中起着关键作用。 肺纤维化，作为生长因子的重要来源， 调节细胞外基质合成。我们假设细胞因子 IL-13至C1O途径促进肺纤维化的机制是 不依赖于IL-13对成纤维细胞的直接作用。的表达方式 IL-13及其受体导致C10的诱导，从而促进 募集特定数量的促纤维化巨噬细胞。具体的 目的如下：1)A)表征C1O的表达和调控 在博莱霉素性肺纤维化的发病机制中起重要作用。 B.确定IL-13和CIO对 肺纤维化的发展。2)比较和对比 IL-4/IL-4R和IL-13/IL-13R AS的配体/受体表达差异 它们涉及到CIO的诱导，以及随后的发展 肺纤维化。3)评估IL-13/IL-13R信号转导途径 这导致了CIO的诱导，并随后发展为肺 纤维化症。4)确定CIO招聘的不同人群 导致肺纤维化的巨噬细胞。5)研究 外源性干扰素-γ对特发性肺纤维化患者的治疗作用 Th1/Th2细胞因子平衡与MIP-18的表达 C1O)，并将这些发现与临床、放射和 疾病活动的生理参数。在这个项目中，既有 将使用博莱霉素和FITC肺纤维化模型。技术以达到 可利用的包括各种分子、免疫学和细胞学 生物检测。成功完成这些具体目标将提供洞察力 进入一条新的巨噬细胞募集途径，可能导致新的 IPF的治疗性干预。

(Applicant's Abstract) The pathogenesis of idiopathic pulmonary fibrosis is charactenized by an intense inflammatory response with accompanying fibroproliferation and deposition of extracellular matrix. The initial stimulus for inflammatory cell recruitment and the mechanisms responsible for the perpetuation and evolution of chronic inflammation, granulation tissue formation, and fibrosis have not been fully elucidated. While IL-13, a Th2 cytokine, has been shown to have direct effects on fibroblasts that supports fibroproliferation it is also a potent inducer of a novel CC chemokine, CIO, which is chemotactic for mononuclear phagocytes. The macrophage/mononuclear phagocyte has been shown to have a pivotal role in the pathogenesis of pulmonary fibrosis, serving as an important source of growth factors that regulate extracellular matrix synthesis. We hypothesize that the cytokine pathway of IL-13 to C1O promotes pulmonary fibrosis via a mechanism that is independent of the direct effect of IL-13 on fibroblasts. The expression of IL-13 and its receptor leads to the induction of C10, which promotes recruitment of a specific population of pro-fibrotic macrophages. The specific aims are as follows: 1)A. To characterize the expression and regulation of C1O during the pathogenesis of bleomycin-induced pulmonary fibrosis. B. To determine the relative and specific contributions of IL-13 and CIO to the development of pulmonary fibrosis. 2) To compare and contrast the disparity between ligand/receptor expression of IL-4/IL4R and IL-13/IL-13R as they relate to the induction of CIO, and the subsequent development of pulmonary fibrosis. 3) To assess IL-13/IL-13R signal transduction pathways that lead to the induction of CIO, and the subsequent development of pulmonary fibrosis. 4) To establish that CIO recruits a distinct population of macrophages that induce pulmonary fibrosis. 5) To study the effect of administration of exogenous interferon-gamma to patients with IPF on the balance of Th1/Th2 cytokines and the expression of MIP-18 (human homologue of C1O), and to correlate these findings with clinical, radiological and physiological parameters of disease activity. In this project both the bleomycin and FITC models of pulmonary fibrosis will be used. Techniques to be employed include a variety of molecular, immunological and cellular bioassays. Successful completion of these specific aims will provide insight into a novel pathway for macrophage recruitment that may lead to new therapeutic interventions in IPF.