Eosinophils in Pulmonary Fibrosis

肺纤维化中的嗜酸性粒细胞

• 批准号: 6465037
• 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/6465037
• 关键词: cell cell interaction; 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）：发生纤维化的发病机制 特发性肺纤维化和哮喘患者的气道仍有待研究 针对这些进行性纤维化过程的有效治疗方法 需要。嗜酸性粒细胞是发病机制中重要的细胞参与者 肺实质和气道纤维化。嗜酸性粒细胞是潜在来源 多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)beta1、TGFalpha、白细胞介素 (IL)-4、 和IL-13；在肺纤维化组织内，记录了嗜酸性粒细胞 纤维化细胞因子的来源，包括 CTGF 和 TGFbeta1。在小鼠模型中 肺纤维化，阻止嗜酸性粒细胞募集的实验方式 和激活导致纤维化减少。因此，嗜酸性粒细胞有助于 肺纤维化发病机制的核心。作为参与者 肺纤维化时，人类嗜酸性粒细胞有几个独特的特征 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库 可从细胞质颗粒快速释放的促纤维化细胞因子 通过囊泡运输。受到严格监管但基本上未定义的 控制预先形成的促纤维化细胞因子的分泌的机制 它们的细胞外释放或嗜酸性粒细胞的质膜表达是 对于理解和控制嗜酸性粒细胞参与肺部疾病至关重要 纤维发生。嗜酸性粒细胞通过近分泌和旁分泌机制可以调节 这些病变中邻近成纤维细胞和其他细胞的功能；和 相反，成纤维细胞和其他细胞是刺激的来源，可以 调节嗜酸性粒细胞功能。中心假设是嗜酸性粒细胞通过 它们的细胞间相互作用及其调节的分泌和 纤维化细胞因子的表达，在纤维化的发病机制中起重要作用 实质和气道肺纤维化。目标是描绘 调节嗜酸性粒细胞分泌和表达的潜在机制 预形成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。确定机制 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，并可能确定适合的步骤 进行治疗干预。