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.
There are no effective therapeutic approaches to limit airway remodeling and interstitial fibrosis. Our proposal brings together experts in surfactant biology, interstitial fibosis and translational asthma research and will provide mechanistic insights into how endogenous host factors regulate chronic inflammation, airway remodeling and interstitial fibrosis in mouse and man with the potential to provide new therapies for these severe diseases.
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