Partial inhibition of integrin alpha v beta 6 prevents pulmonary fibrosis without exacerbating inflammation

Rationale Transforming growth factor (TGF)-beta has a central role in driving many of the pathological processes that characterize pulmonary fibrosis. Inhibition of the integrin alpha v beta 6, a key activator of TGF-beta in lung, is an attractive therapeutic strategy, as it may be possible to inhibit TGF-beta at sites of alpha v beta 6 up-regulation without affecting other homeostatic roles of TGF-beta. Objectives: To analyze the expression of alpha v beta 6 in human pulmonary fibrosis, and to functionally test the efficacy of therapeutic inhibition of alpha v beta 6-mediated TGF-beta activation in murine bleomycin-induced pulmonary fibrosis. Methods: Lung biopsies from patients with a diagnosis of systemic sclerosis or idiopathic pulmonary fibrosis were stained for alpha v beta 6 expression. A range of concentrations of a monoclonal antibody that blocks alpha v beta 6-mediated TGF-beta activation was evaluated in murine bleomycin-induced lung fibrosis. Measurements and Main Results: alpha v beta 6 is overexpressed inhuman lung fibrosis within pneumocytes lining the alveolar ducts and alveoli. In the bleomycin model, alpha v beta 6 antibody was effective in blocking pulmonary fibrosis. At high doses, there was increased expression of markers of inflammation and macrophage activation, consistent with the effects of TGF-beta inhibition in the lung. Low doses of antibody attenuated Collagen expression without increasing alveolar inflammatory cell populations or macrophage activation markers. Conclusions: Partial inhibition of TGF-beta using alpha v beta 6 integrin antibodies is effective in blocking murine pulmonary fibrosis without exacerbating inflammation. In addition, the elevated expression of alpha v beta 6, an activator of the fibrogenic cytokine, TGF-beta, in human pulmonary fibrosis suggests that alpha v beta 6 monoclonal antibodies could represent a promising new therapeutic strategy for treating pulmonary fibrosis.