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

Abstract

Rationale: In experimental models, lung fibrosis is dependent on transforming growth factor (TGF)-b signaling. TGF-b is secreted in a latent complex with its propeptide, and TGF-b activators release TGF-b from this complex. Because the integrin avb6 is a major TGF-b activator in the lung, inhibition of avb6-mediated TGF-b 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 avb6. Methods: Wild-type mice, avb6-deficient (Itgb6 2/2 ) mice, and mice heterozygous for a Tgfb1 mutation that eliminates integrin-mediated activation (Tgfb1 1/RGE ) were exposed to 14 Gy thoracic radiation. Some mice were treated with an anti-avb6 monoclonal antibody or a soluble TGF-b receptor fusion protein. avb6 expression was determined by immunohistochemistry. Fibrosis, inflammation, and gene expression patterns were assessed 20-32 weeks postirradiation. Measurements and Main Results: b6 Integrin expression increased within the alveolar epithelium 18 weeks postirradiation, just before onset of fibrosis. Itgb6 2/2 mice were completely protected from fibrosis, but not from late radiation-induced mortality. Anti-avb6 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 2/2 mice. Tgfb1-haploinsufficient mice were also protected from fibrosis. Conclusions: avb6-Mediated TGF-b activation is required for radiationinduced lung fibrosis. Together with previous data, our results demonstrate a robust requirement for avb6 in distinct fibrosis models. Inhibition of avb6-mediated TGF-b activation is a promising new approach for antifibrosis therapy.

Preclinical SPECT/CT Imaging of αvβ6 Integrins for Molecular Stratification of Idiopathic Pulmonary Fibrosis

“…Novel strategies to improve the outcome for these patients are urgently required, and to facilitate a stratified approach to the treatment of IPF it is important to identify a biomarker that reflects relevant biology. The epithelial-restricted integrin avb6 is an attractive target for the treatment of IPF because of its important role in regulating integrin-dependent transforming growth factor b activation (25), its pathogenic role in several different experimental models of fibrosis (25,26,28,(35)(36)(37), and its increased expression on alveolar epithelial cells in fibrotic areas of lung in patients with IPF (27,28). The expression of avb6 integrin is temporally and spatially linked to the development of fibrosis, with upregulation of integrin in the alveolar epithelium being detected before the development of fibrosis and persisting within the fibrotic lesions (26).…”

“…The avb6 integrin has been implicated in multiple models of lung fibrosis (25)(26)(27), as well as being upregulated in patients with IPF (27,28), and there is some evidence to suggest that levels may vary between patients with differing interstitial lung diseases (28). Targeting this molecule has considerable therapeutic potential (25,28), and a clinical trial is currently in progress (NCT01371305; ClinicalTrials.gov).…”

Cross Talk among TGF- Signaling Pathways, Integrins, and the Extracellular Matrix

“…This is caused by lack of TGF-bmediated inhibition of MMP12 expression in alveolar macrophages and resultant elastin degradation. However, Itgb6 -/ -mice are protected from experimental fibrosis and lung injury associated with increased TGF-b signaling (Pittet et al 2001;Puthawala et al 2008).…”

Radiation-Induced Lung Response of AcB/BcA Recombinant Congenic Mice

“…Herein we investigated the response of Ja18 -/-mice (which exclusively lack type I NKT cells (19)] to thoracic radiation therapy. We compared the response of these mice to that of the background strain, C57BL/6J an inbred strain which we (20)(21)(22) and others (23,24) have shown succumbs to fibrosing alveolitis after thoracic irradiation. Although C57BL/6J mice are commonly used in pulmonary response studies, one group (25) suggests the response of this strain may have limitations.…”