Inhibition of integrin alpha v beta 6, an activator of latent transforming growth factor-beta, prevents radiation-induced lung fibrosis

Rationale In experimental models, lung fibrosis is dependent on transforming growth factor (TGF)-beta signaling. TGF-beta is secreted in a latent complex with its propeptide, and TGF-beta activators release TGF-beta from this complex. Because the integrin alpha v beta 6 is a major TGF-beta activator in the lung, inhibition of alpha v beta 6-mediated TGF-beta activation is a logical strategy to treat lung fibrosis. Objectives: To determine, by genetic and pharmacologic approaches, whether murine radiation-induced lung fibrosis is dependent on alpha v beta 6. Methods: Wild-type mice, alpha v beta 6-deficient (Itgb6(-/-)) mice, and mice heterozygous for a Tgfb1 mutation that eliminates integrin-mediated activation (Tgfb 1(+/RGE)) were exposed to 14 Gy thoracic radiation. Some mice were treated with an anti-alpha v beta 6 monoclonal antibody or a soluble TGF-beta receptor fusion protein. alpha v beta 6 expression was determined by immunohistochemistry. Fibrosis, inflammation, and gene expression patterns were assessed 20-32 weeks postirradiation. Measurements and Main Results: beta 6 Integrin expression increased within the alveolar epithelium 18 weeks postirradiation, just before onset of fibrosis. Itgb6(-/-) mice were completely protected from fibrosis, but not from late radiation-induced mortality. Anti-alpha v beta 6 therapy (1-10 mg/kg/wk) prevented fibrosis, but only higher doses (6-10 mg/kg/wk) caused lung inflammation similar to that in Itgb6(-/-)mice. Tgfb 1-haploinsufficient mice were also protected from fibrosis. Conclusions: alpha v beta 6-Mediated TGF-beta activation is required for radiation-induced lung fibrosis. Together with previous data, our results demonstrate a robust requirement for alpha v beta 6 in distinct fibrosis models. Inhibition of alpha v beta 6-mediated TGF-beta activation is a promising new approach for antifibrosis therapy.