Inhibition of Integrin αvβ6, an Activator of Latent Transforming Growth Factor-β, Prevents Radiation-induced Lung Fibrosis

• Published in: American journal of respiratory and critical care medicine Vol. 177; no. 1; pp. 82 - 90
• Main Authors: PUTHAWALA, Khalid, HADJIANGELIS, Nicos, VIOLETTE, Shelia M, GRANT, Kristen S, COLAROSSI, Cristina, FORMENTI, Silvia C, MUNGER, John S, JACOBY, Steven C, BAYONGAN, Emmanuel, ZHICHENG ZHAO, ZHIWEI YANG, DEVITT, Mary Louise, HORAN, Gerald S, WEINREB, Paul H, LUKASHEV, Matvey E
• Format: Journal Article
• Language: English
• Published: New York, NY American Lung Association 01.01.2008; American Thoracic Society
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Blood and lymphatic vessels; Blood. Blood coagulation. Reticuloendothelial system; Cardiology. Vascular system; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; E. Interstitial Lung Disease; Intensive care medicine; Medical sciences; Pharmacology. Drug treatments; Latent; Intensive care; Pulmonary fibrosis; Integrin; Transforming growth factor β; Inflammation; Monoclonal antibody; Lymphocyte; Resuscitation
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200706-806OC

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 αvβ6 is a major TGF-β activator in the lung, inhibition of αvβ6-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 αvβ6. Methods : Wild-type mice, αvβ6-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-αvβ6 monoclonal antibody or a soluble TGF-β receptor fusion protein. αvβ6 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-αvβ6 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 : αvβ6-Mediated TGF-β activation is required for radiation-induced lung fibrosis. Together with previous data, our results demonstrate a robust requirement for αvβ6 in distinct fibrosis models. Inhibition of αvβ6-mediated TGF-β activation is a promising new approach for antifibrosis therapy.