Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease

描述（由申请人提供）： 该计划项目资助申请将测试以下假设：在急性非感染性肺损伤或过敏性炎症的背景下产生的内源性宿主因子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起着重要作用。形成该提议基础的合作研究表明，细胞外基质糖胺聚糖透明质酸（HA）是在非感染性急性肺损伤和慢性吸入性过敏原暴露的背景下产生的。待检验的总体假设是，当未检查时，在损伤的肺中积累的基质片段将传播炎症并促进导致侵袭性成纤维细胞表型出现的环境，所述侵袭性成纤维细胞表型导致肺功能的不可逆丧失。每个项目将探索不同的，但互补的和顺序的过程，这一拟议的炎症级联反应。表面活性蛋白是抵抗过度炎症的第一波防御。在不存在SP-A和SP-D的情况下，HA片段积累增加，并且炎症和纤维化都更严重，导致肺功能的不可逆丧失。项目2（Wright）关注SP-A和SP-D干扰基质驱动的炎症并拮抗关键促纤维化介质（如TGF-β）的功能的机制。HA产生的重要来源是间充质细胞。当肌成纤维细胞被靶向以在小鼠中过表达透明质酸合酶2（HAS 2）时，产生严重的表型，导致HA积累、持续的炎症和纤维破坏性肺病，死亡率增加。项目1（Noble）将使用新的遗传模型确定HAS 2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组成型产生HA片段，并获得侵袭性表型，以响应IL-13。项目3（Kraft）研究了HA和IL-13调节人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，即宿主因子的相互作用调节炎症和纤维化肺病。

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.