Inhibition of integrin αvβ6, an activator of latent transforming growth factor-β, prevents radiation-induced lung fibrosis
K Puthawala, N Hadjiangelis, SC Jacoby… - American journal of …, 2008 - atsjournals.org
K Puthawala, N Hadjiangelis, SC Jacoby, E Bayongan, Z Zhao, Z Yang, ML Devitt, GS Horan…
American journal of respiratory and critical care medicine, 2008•atsjournals.orgRationale: 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 …
(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 …
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.
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