Abstract The molecular mechanisms that control stem cell renewal and tissue fibrosis remain incompletely understood. This program is our continuous effort to elucidate the role of extracellular matrix components and innate immune receptors in regulating lung injury, inflammation, and fibrosis. Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease resulting, in part, from inadequate alveolar epithelial repair leading to detonation of excessive fibroblast activity. Our laboratory has generated a body of work during the last founding period showing that glycosaminoglycan hyaluronan (HA) and innate immune receptor TLR4 expressed on alveolar epithelial cells and macrophages have important roles in regulating lung inflammation and fibrosis in the context of noninfectious lung injury. HA is synthesized at the cell membrane by hyaluronan synthase 2 (HAS2). We have discovered that HA expressed on the cell surface of lung epithelial cells serves a protective function against noninfectious insults that is dependent upon TLR4. The new findings that lead us to forms the basis for this renewal application is that innate immune receptors interact with endogenous extracellular matrix to promote alveolar progenitor cell renewal. During the past several years, our team has developed state-of-the- art tools to target both Type 2 alveolar epithelial cells (AEC2s) in the context of noninfectious lung injury. During the funding period of this award, we discovered that mice deficient in either TLR4 or with a targeted deletion of HAS2 in AEC2s are enormously sensitive to non-infectious lung injury and develop fulminant interstitial fibrosis. AEC2s isolated from mice deficient in either TLR4 or with a targeted deletion of HAS2 show reduced self-renewal capacity. We show for the first time, that innate immune receptors interacting with matrix are necessary for lung stem cell renewal and prevention of severe fibrosis. We have identified IL-6 as a putative cytokine mediator released by AEC2s in a manner dependent on HA-TLR4 interactions promotes stem cell renewal and modulates lung fibrosis. Most importantly, we have found that there is a significant reduction of AEC2s from the lung of patients with IPF compared to the lung of healthy donors. AEC2s from the IPF lungs showed reduced cell surface HA and impaired renewal capacity relative to the cells from healthy lungs. These data further support the concept that IPF is a disease of AEC2 failure and our mouse model recapitulates key aspects of the human lung fibrotic disease. Based on our preliminary studies, we have generated the hypothesis that interactions between cell surface HA and its receptors are essential components of AEC2 progenitor cell renewal and lung re...