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Published ahead of print on October 4, 2007, doi:10.1164/rccm.200706-806OC

Am. J. Respir. Crit. Care Med., Volume 177, Number 1, January 2008, 82-90

A more recent version of this article appeared on January 1, 2008
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Submitted on June 1, 2007
Accepted on October 4, 2007

Inhibition of Integrin {alpha}v{beta}6, an Activator of Latent TGF{beta}, Prevents Radiation-Induced Lung Fibrosis

Khalid Puthawala1, Nicos Hadjiangelis1, Steven C Jacoby1, Emmanuel Bayongan1, Zhicheng Zhao2, Zhiwei Yang2, Mary Louise Devitt3, Gerald S Horan4, Paul H Weinreb4, Matvey E Lukashev4, Shelia M Violette4, Kristen S Grant2, Cristina Colarossi2, Silvia C Formenti3, and John S Munger5*

1 Department of Medicine, New York University School of Medicine, New York, NY, USA, 2 Department of Cell Biology, New York University School of Medicine, New York, NY, USA, 3 Department of Radiation Oncology, New York University School of Medicine, New York, NY, USA, 4 Biogen Idec, Cambridge, MA, USA, 5 Department of Medicine, New York University School of Medicine, New York, NY, USA; Department of Cell Biology, New York University School of Medicine, New York, NY, USA

* To whom correspondence should be addressed. E-mail: john.munger{at}med.nyu.edu.

Rationale: In experimental models, lung fibrosis is dependent upon 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. Objective: To determine, by genetic and pharmacologic approaches, whether murine radiation-induced lung fibrosis is dependent upon {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 (Tgfb1+/RGE) were exposed to 14 Gy thoracic radiation. Some mice were treated with an anti-{alpha}v{beta}6 mAb 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 post-irradiation. Measurements and main results: {beta}6 integrin expression increased within the alveolar epithelium 18 weeks post-irradiation, just prior to 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. Tgfb1-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 anti-fibrosis therapy.
Key words: inflammation, monoclonal antibody, lymphocyte




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