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Inhibition of Integrin vβ6, an Activator of Latent Transforming Growth Factor-β, Prevents Radiation-induced Lung Fibrosis

Departments of ¹ Medicine, ² Cell Biology, and ³ Radiation Oncology, New York University School of Medicine, New York, New York; and ⁴ Biogen Idec, Cambridge, Massachusetts

Correspondence and requests for reprints should be addressed to John S. Munger, M.D., New York University School of Medicine, Department of Cell Biology, MSB607, 550 First Avenue, New York, NY 10282. E-mail: john.munger{at}med.nyu.edu

Rationale: In experimental models, lung fibrosis is dependent on transforming growth factor (TGF)-β signaling. TGF-β is secreted in a latent complex with its propeptide, and TGF-β activators release TGF-β from this complex. Because the integrin vβ6 is a major TGF-β activator in the lung, inhibition of vβ6-mediated TGF-β 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 vβ6.

Methods: Wild-type mice, vβ6-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-vβ6 monoclonal antibody or a soluble TGF-β receptor fusion protein. vβ6 expression was determined by immunohistochemistry. Fibrosis, inflammation, and gene expression patterns were assessed 20–32 weeks postirradiation.

Measurements and Main Results: β6 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-vβ6 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: vβ6-Mediated TGF-β activation is required for radiation-induced lung fibrosis. Together with previous data, our results demonstrate a robust requirement for vβ6 in distinct fibrosis models. Inhibition of vβ6-mediated TGF-β activation is a promising new approach for antifibrosis therapy.

Key Words: inflammation • lymphocyte • monoclonal antibody

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Transforming growth factor (TGF)-β is a profibrotic cytokine, and its latent form is activated by the integrin vβ6 in the lung. A monoclonal antibody has been developed that potently and specifically inhibits vβ6. What This Study Adds to the Field Inhibition of vβ6-mediated TGF-β activation prevents murine radiation–induced lung fibrosis, and the antifibrotic effect is achieved at doses lower than those that cause lung inflammation due to loss of TGF-β's immunomodulatory effects.

 

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Partial Inhibition of Integrin vβ6 Prevents Pulmonary Fibrosis without Exacerbating Inflammation

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AJRCCM 2008 177: 56-65. [Abstract] [Full Text]  

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