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Published ahead of print on October 4, 2007, doi:10.1164/rccm.200706-805OC

Am. J. Respir. Crit. Care Med., Volume 177, Number 1, January 2008, 56-65

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Submitted on June 1, 2007
Accepted on October 4, 2007

Partial Inhibition of Integrin {alpha}v{beta}6 Prevents Pulmonary Fibrosis Without Exacerbating Inflammation

Gerald S Horan1*, Susan Wood1, Victor Ona1, Dan Jun Li1, Matvey E Lukashev1, Paul H Weinreb1, Kenneth J Simon1, Kyungmin Hahm1, Normand E Allaire1, Nicola J Rinaldi1, Jaya Goyal1, Carol A Feghali-Bostwick2, Eric L Matteson3, Carl O'Hara4, Robert Lafyatis4, Gerald S Davis5, Xiaozhu Huang6, Dean Sheppard6, and Shelia M Violette1

1 Departments of Exploratory Biology, Fibrosis, Protein Chemistry, Gene Discovery, Molecular Profiling, and Clinical Sciences and Technology, Biogen Idec, Cambridge, MA, USA, 2 Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA, 3 Division of Rheumatology, Mayo Clinic, Rochester, MN, USA, 4 Section of Rheumatology, Department of Pathology, Boston University School of Medicine, Boston, MA, USA, 5 Pulmonary Disease and Critical Care Medicine, University of Vermont, Burlington, VT, USA, 6 Lung Biology Center, University of California San Francisco, San Francisco, CA, USA

* To whom correspondence should be addressed. E-mail: gerald.horan{at}biogenidec.com.

Rationale: 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 upregulation 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 (IPF) 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. Results: {alpha}v{beta}6 is overexpressed in human 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 av{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.
Key words: TGF-beta, Integrin, alphavbeta6, fibrosis




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