Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease

描述(由申请人提供)： 本计划项目赠款申请将检验这样一种假设，即在急性非传染性肺损伤或过敏性炎症的背景下产生的内源性宿主因素在与肺纤维化和哮喘等疾病相关的炎症和纤维化的启动和维持中发挥基本作用。构成这一建议基础的合作研究表明，细胞外基质糖胺聚糖透明质酸(HA)是在非传染性急性肺损伤和慢性吸入性变应原暴露的背景下产生的。需要检验的总体假设是，如果不加以控制，在受损肺中积累的基质片段将促进炎症并促进环境，导致侵袭性成纤维细胞表型的出现，从而导致不可逆转的肺功能丧失。每个项目都将探索这一提议的炎症级联的不同的、但互补的和顺序的过程。在对抗过度炎症的第一波防御中，表面活性蛋白质就是其中之一。在没有SP-A和SP-D的情况下，HA片段堆积增加，炎症和纤维化都更加严重，导致不可逆转的肺功能丧失。项目2(Wright)侧重于SP-A和SP-D干预基质驱动的炎症和拮抗关键的促纤维化介质如转化生长因子-β的功能的机制。HA产生的一个重要来源是间充质细胞。当以肌成纤维细胞为靶点在小鼠体内过表达透明质酸合成酶2(HAS2)时，会产生严重的表型，导致HA积聚，持续炎症和纤维破坏性肺疾病，并增加死亡率。项目1(Noble)将使用新的遗传模型确定HAS2促进气道重塑和间质纤维化的机制。哮喘患者的成纤维细胞在IL-13的作用下会结构性地产生HA片段并获得侵袭性表型。项目3(KRAFT)研究了HA和IL-13调节人类和小鼠哮喘表型发展的机制。这些项目中的每一个都有一个共同的主题，即宿主因素的相互作用调节炎症和纤维化的肺部疾病。

DESCRIPTION (provided by applicant): This Program Project Grant application will test the hypothesis that endogenous host factors generated in the context of either acute non-infectious lung injury or allergic inflammation play a fundamental role in the initiation and maintenance of inflammation and fibrosis associated with diseases such as pulmonary fibrosis and asthma. The collaborative studies that form the foundation of this proposal have shown that the extracellular matrix glycosaminoglycan hyaluronan (HA) is generated in the context of non-infectious acute lung injury and chronic inhaled allergen exposure. The overall hypothesis to be tested is that when unchecked, matrix fragments accumulating in the injured lung will propogate inflammation and facilitate an environment leading to the emergence of an invasive fibroblast phenotype that causes irreversible loss of lung function. Each project will probe different, yet complementary and sequencial processes of this proposed inflammatory cascade. Among the first wave of defense against excess inflammation are surfactant proteins. In the absence of SP-A and SP-D, HA fragment accumulation is augmented and both inflammation and fibrosis are more severe leading to irreversible loss of lung function. Project 2 (Wright) focuses on the mechanisms by which SP-A and SP-D interfere with matrix-driven inflammation and antagonize the functions of critical pro-fibrotic mediators such as TGF-beta. An important source of HA production are mesenchymal cells. When myofibroblasts are targeted to over-express hyaluronan synthase 2 (HAS2) in the mouse, a severe phenotype is generated leading to HA accumulation, unremitting inflammation and fibrodestructive lung disease with increased mortality. Project 1 (Noble) will determine the mechanisms by which HAS2 promotes airway remodeling and interstitial fibrosis using novel genetic models. Fibroblasts from asthmatic patients constitutively produce HA fragments and acquire an invasive phenotype in response to IL-13. Project 3 (Kraft) investigates the mechanisms by which HA and IL-13 regulate the development of the asthma phenotype in both man and mouse. Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases.