Radiation-induced pulmonary fibrosis (RIPF) is one of the major dose-limiting toxicities of thoracic radiation. It is generally believed that the fibrogenic cytokine TGFbeta1 is necessary for the development of RIPF, although this hypothesis has not been directly tested in animal models. Because TGFbeta1 is secreted in a latent form, TGFbeta1 activity is controlled by an activation step. TGFbeta1 latency is due to interaction of TGFbeta1 with its propeptide, Latency-Associated Peptide (LAP). TGFbeta1 signaling occurs following release of TGFbeta1 from LAP. We discovered that LAP is a ligand for an epithelium-specific integrin, alphavbeta6. Following ligation of LAP by alphavbeta6, TGFbeta1 is released. Therefore, by expressing alphavbeta6, epithelial cells locally activate TGFbeta1. Mice lacking alphavbeta6 (beta6-/- mice) do not develop lung fibrosis after exposure to bleomycin. Recently, we generated mice with a knocked-in mutation in TGFbeta1-LAP that abrogates integrin binding (TGFbeta1-RGE mice). The phenotype of these mice reproduces that of TGFbeta1-/- mice, indicating that integrin-mediated TGFbeta1 activation is a major (and perhaps the only) mechanism for generating active TGFbeta1. We have also found that beta6-/- mice do not develop RIPF. Furthermore, wild type mice sharply upregulate alphavbeta6 expression in lung epithelium as a late event after thoracic irradiation, just prior to the onset of RIPF. These results suggest that alphavbeta6-mediated TGFbeta1 activation is required for RIPF, and suggest 2 treatment strategies: inhibition of alphavbeta6 function, and prevention of alphavbeta6 upregulation. Our overall goal is to treat and/or prevent RIPF by inhibiting the alphavbeta6-TGFbeta1 activation system. We propose 3 aims. First, we will confirm that TGFbeta1 is required for RIPF. This will be done by treating irradiated mice with a TGFbeta antagonist and also by measuring the fibrotic response of TGFbeta1+/- mice. Second, we will test whether an alphavbeta6 inhibitor (a murine anti-alphavbeta6 mAb) reverses and/or prevents RIPF. If this reagent works, it should be considered as a potential therapy in human RIPF, and perhaps in radiation fibrosis affecting other organs. Measuring the fibrotic response of TGFbeta1-RGE+/- mice will also test the role of integrin-mediated TGFbeta1 activation in RIPF. Third, we will test the hypothesis that alphavbeta6 upregulation in lung epithelium, which occurs just prior to the development of RIPF, is due to increased TGFbeta1 signaling.
| Aluwihare, Poshala; Munger, John S (2008) What the lung has taught us about latent TGF-beta activation. Am J Respir Cell Mol Biol 39:499-502 |
| Puthawala, Khalid; Hadjiangelis, Nicos; Jacoby, Steven C et al. (2008) Inhibition of integrin alpha(v)beta6, an activator of latent transforming growth factor-beta, prevents radiation-induced lung fibrosis. Am J Respir Crit Care Med 177:82-90 |
