Eosinophils in Pulmonary Fibrosis

肺纤维化中的嗜酸性粒细胞

• 批准号: 6731179
• 负责人: PETER F WELLER
• 金额: $ 38.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-31 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6731179
• 关键词: cell cell interaction; clinical research; cytokine; eosinophil; fibroblasts; fibrogenesis; growth factor; human subject; interleukin 13; interleukin 4; pathologic process; pulmonary fibrosis /granuloma; tissue /cell culture; transforming growth factors

DESCRIPTION (provided by applicant): The pathogenesis of fibrosis that develops in idiopathic pulmonary fibrosis and the airways of asthmatics remains to be delineated, and effective treatments for these progressive fibrotic processes are needed. Eosinophils are important cellular participants in the pathogenesis of parenchymal and airway pulmonary fibrosis. Eosinophils are potential sources of several profibrotic cytokines, including connective tissue growth factor (CTGF), transforming growth factor (TGF)beta1, TGFalpha, interleukin (IL)-4, and IL-13; and within pulmonary fibrotic tissues, eosinophils are documented sources of fibrogenic cytokines, including CTGF and TGFbeta1. In murine models of pulmonaryfibrosis, experimental modalities that block eosinophil recruitment and activation have led to decreased fibrosis. Thus, eosinophils contribute centrally to the pathogenesis of pulmonary fibrosis. As participants in pulmonary fibrosis, human eosinophils have several distinct and unique functional capabilities. Notably, eosinophils contain already preformed stores of profibrotic cytokines that are rapidly releasable from cytoplasmic granules by means of vesicular transport. The highly regulated, but largely undefined, mechanisms that govern the secretion of preformed profibrotic cytokines for their extracellular release or plasma membrane expression by eosinophils are central to the understanding and control of eosinophil involvement in pulmonary fibrogenesis. Eosinophils by juxtacrine and paracrine mechanisms can modulate the functioning of adjacent fibroblasts and other cells in these lesions; and conversely, fibroblasts and other cells are sources of stimuli that can modulate eosinophil functioning. The central hypothesis is that eosinophils, by means of their cell-cell interactions and their regulated secretion and expression of fibrogenic cytokines, have major roles in the pathogenesis of parenchymal and airway pulmonary fibrosis. The aims are to delineate the underlying mechanisms that regulate eosinophil secretion and expression of preformed profibrotic cytokines and to investigate functional interactions between eosinophils and lung fibroblasts. Determining the mechanisms that govern eosinophil-fibroblast interactions will help to understand the development of parenchymal or airway fibrosis and may identify steps amenable to therapeutic interventions.

描述（由申请人提供）：纤维化的发病机制， 在特发性肺纤维化和哮喘患者的气道中， 描述了这些进行性纤维化过程的有效治疗方法 是必要的。嗜酸性粒细胞是重要的细胞参与者的发病机制 肺实质和气道纤维化。嗜酸性粒细胞是 几种促纤维化细胞因子，包括结缔组织生长因子 （CTGF）、转化生长因子（TGF）β 1、TGF α、白细胞介素（IL）-4， 和IL-13;在肺纤维化组织中，记录了嗜酸性粒细胞 纤维化细胞因子的来源，包括CTGF和TGF β 1。鼠模型中 肺纤维化，阻断嗜酸性粒细胞募集的实验方法 和活化导致纤维化减少。因此，嗜酸性粒细胞 肺纤维化的发病机制。是参政党 肺纤维化，人类嗜酸性粒细胞有几个不同的和独特的 功能能力。值得注意的是，嗜酸性粒细胞含有已经预先形成的储存， 从细胞质颗粒中快速释放的促纤维化细胞因子 通过囊泡运输。受到高度监管，但基本上没有定义， 控制预先形成的促纤维化细胞因子分泌的机制， 它们的细胞外释放或由嗜酸性粒细胞的质膜表达， 嗜酸性粒细胞参与肺部疾病的理解和控制的中心 纤维化嗜酸性粒细胞通过旁分泌和非分泌机制调节 这些病变中相邻成纤维细胞和其他细胞的功能;以及 相反，成纤维细胞和其他细胞是刺激源， 调节嗜酸性粒细胞功能。核心假设是嗜酸性粒细胞， 它们的细胞-细胞相互作用及其调节分泌的方式， 纤维化细胞因子的表达，在纤维化的发病机制中起主要作用。 实质和气道肺纤维化。目的是描绘 调节嗜酸性粒细胞分泌和表达的潜在机制 预制的促纤维化细胞因子，并研究功能相互作用 嗜酸性粒细胞和肺成纤维细胞之间的关系。确定 控制嗜酸性粒细胞-成纤维细胞相互作用将有助于理解 实质或气道纤维化的发展，并可能确定可行的步骤 到治疗干预。