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
A more recent version of this article appeared on January 1, 2008
Submitted on June 1, 2007
Accepted on October 4, 2007
Partial Inhibition of Integrin v 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- has a central role in driving many of the pathological processes that characterize pulmonary fibrosis. Inhibition of the integrin v 6, a key activator of TGF- in lung, is an attractive therapeutic strategy, as it may be possible to inhibit TGF- at sites of v 6 upregulation without affecting other homeostatic roles of TGF- .
Objectives: To analyze the expression of v 6 in human pulmonary fibrosis, and to functionally test the efficacy of therapeutic inhibition of v 6-mediated TGF- 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 v 6 expression. A range of concentrations of a monoclonal antibody that blocks v 6-mediated TGF- activation was evaluated in murine bleomycin-induced lung fibrosis.
Results: v 6 is overexpressed in human lung fibrosis within pneumocytes lining the alveolar ducts and alveoli. In the bleomycin model, v 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- 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- using v 6 integrin antibodies is effective in blocking murine pulmonary fibrosis without exacerbating inflammation. In addition, the elevated expression of av 6, an activator of the fibrogenic cytokine, TGF- , in human pulmonary fibrosis suggests that v 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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Y. Song, J. F. Pittet, X. Huang, H. He, S. V. Lynch, S. M. Violette, P. H. Weinreb, G. S. Horan, A. Carmago, Y. Sawa, et al.
Role of Integrin {alpha}v{beta}6 in Acute Lung Injury Induced by Pseudomonas aeruginosa
Infect. Immun.,
June 1, 2008;
76(6):
2325 - 2332.
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Copyright © 2007 American Thoracic Society
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