UCSF

Idiopathic pulmonary fibrosis (IPF), or scarring of the lungs, is an incurable progressive disease that has a 5-year mortality rate of 80%. The cytokine, Transforming Growth Factor Beta (TGF-β) is considered a central mediator in the pathogenesis of this fibrotic disorder. Virtually all cells secrete TGF-β as a latent complex that must be activated for the cytokine to exert its biological functions. We previously discovered that the integrin αvβ6 functions to activate TGF-β. However, the signals and mechanisms that regulate this process in epithelial cells are unclear. We discovered that the phospholipid, Sphingosine 1-Phosphate (S1P), induces αvβ6-mediated TGF-β activation by increasing Rho Kinase (ROCK)-mediated actomyosin contraction. Furthermore, we demonstrate that this process requires intracellular mechanical forces applied to the integrin and the generation of cellular tension. Interestingly, lung epithelial cells appear to exert force on latent TGF-β using sub-cortical actin rather than the actin stress fibers utilized by fibroblasts and other traditionally "contractile" cells. In addition, we show that aerosol delivery of small molecule ROCK inhibitors to wild type mice is an effective method of blocking TGF-β signaling in vivo. Finally, we report six candidate biomarkers of inhibiting αvβ6-mediated TGF-β activation and demonstrate the potential of utilizing alveolar macrophages as a biosensor for monitoring this pathway. These findings enhance our understanding of the mechanisms that regulate αvβ6-mediated TGF-β activation, and they demonstrate the potential of blocking this pathway in vivo and monitoring the effectiveness of blockade, defining a potential strategy for developing improved treatments for pulmonary fibrosis.