Eosinophils in Pulmonary Fibrosis

描述(申请人提供)：发生纤维化的发病机制 在特发性肺纤维化和哮喘患者的呼吸道中仍有待于 对这些进行性纤维化过程的描述和有效的治疗 都是需要的。嗜酸性粒细胞是发病机制中的重要细胞参与者。 实质性和气道性肺纤维化。嗜酸性粒细胞是潜在的来源 包括结缔组织生长因子在内的几种促纤维化细胞因子 CTGF、转化生长因子β1、转化生长因子α、白介素4、 和IL-13；在肺纤维化组织中，发现有嗜酸性粒细胞 肝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 和激活导致了纤维化的减少。因此，嗜酸性粒细胞对 在肺纤维化的发病机制中处于中心地位。作为以下项目的参与者 肺纤维化，人类嗜酸性粒细胞有几种截然不同的独特之处 功能功能。值得注意的是，嗜酸性粒细胞含有已经预先形成的储存物 可从胞浆颗粒中快速释放的促纤维化细胞因子 通过囊泡运输的方式。高度监管，但在很大程度上没有定义， 促纤维细胞因子分泌机制的研究进展 嗜酸性粒细胞的胞外释放或质膜表达 嗜酸性粒细胞参与肺间质纤维化的认识和控制 纤维化。嗜酸性粒细胞通过旁分泌和旁分泌机制调节 邻近成纤维细胞和其他细胞在这些病变中的功能；以及 相反，成纤维细胞和其他细胞是刺激的来源，可以 调节嗜酸性粒细胞的功能。中心假说是嗜酸性粒细胞，通过 它们的细胞-细胞相互作用及其调节分泌的手段和 纤维化细胞因子的表达在糖尿病的发病机制中起着重要作用 实质性和气道性肺纤维化。其目的是勾勒出 调节嗜酸性粒细胞分泌和表达的潜在机制 预先形成的促纤维化细胞因子和研究功能相互作用 嗜酸性粒细胞和肺成纤维细胞之间。确定哪些机制 控制嗜酸性粒细胞-成纤维细胞的相互作用将有助于理解 实质或呼吸道纤维化的发展，并可确定可遵循的步骤 到治疗性干预。

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.