The lung, along with the skin and gut are the three organs in perpetual contact with our environment. The lung has evolved mechanisms for repairing injury due to exogenous noxious agents. The timely repair of lung injury is essential and determines the outcome of life or death. The mechanisms that regulate mature alveolar epithelial stem cell renewal are unknown. Our preliminary studies have led to the hypothesis that interactions between components of the innate immune system expressed by lung alveolar epithelial cells and the cell surface glycosaminoglycan hyaluronan are essential for stem cell renewal and lung repair after injury, and loss of this interaction results in severe lung fibrosis. In this proposal, we will define the mechanisms by which innate immune components, as well as endogenous matrix in lung alveolar epithelial cells promote progenitor cell renewal and lung repair. This is the first link between innate immunity and lung stem cell renewal. Elucidating the mechanisms by which endogenous matrix and innate immune components interact to promote stem cell renewal could lead to novel therapeutic approaches to lung diseases. During the first year of funding, we generated necessary reagents in the lab for all the aims of the project. We have made progress in characterization of alveolar epithelial cells from the mice lacking either innate immune receptors or extrecellular matrix hyaluronan synthase. We have also identified necessary cytokines for progenitor cell repair. Furthermore, we observed a difference in lung progenitor cells, as well as cell surface hyaluronan, from patients with progressive lung fibrosis relative to normal donor lungs.