Inhibition of TGF1 activation prevents radiation-induced lung fibrosis

Background: Radiotherapy is the main treatment modality for thoracic tumours, but it may induce pulmonary fibrosis. Currently, the pathogenesis of radiation-induced pulmonary fibrosis (RIPF) is unclear, and effective treatments are lacking. Transforming growth factor beta 1 (TGF beta 1) plays a central role in RIPF. We found that activated TGF beta 1 had better performance for radiation pneumonitis (RP) risk prediction by detecting activated and total TGF beta 1 levels in patient serum. alpha v integrin plays key roles in TGF beta 1 activation, but the role of alpha v integrin-mediated TGF beta 1 activation in RIPF is unclear. Here, we investigated the role of alpha v integrin-mediated TGF beta 1 activation in RIPF and the application of the integrin antagonist cilengitide to prevent RIPF.Methods: Itgav(loxP/loxP);Pdgfrb-Cre mice were generated by conditionally knocking out Itgav in myofibroblasts, and wild-type mice were treated with cilengitide or placebo. All mice received 16 Gy of radiation or underwent a sham radiation procedure. Lung fibrosis was measured by a modified Ashcroft score and microcomputed tomography (CT). An enzyme-linked immunosorbent assay (ELISA) was used to measure the serum TGF beta 1 concentration, and total Smad2/3 and p-Smad2/3 levels were determined via Western blotting.Results: Conditional Itgav knockout significantly attenuated RIPF (p < .01). Hounsfield units (HUs) in the lungs were reduced in the knockout mice compared with the control mice (p < .001). Conditional Itgav knockout decreased active TGF beta 1 secretion and inhibited fibroblast p-Smad2/3 expression. Exogenous active TGF beta 1, but not latent TGF beta 1, reversed these reductions. Furthermore, cilengitide treatment elicited similar results and prevented RIPF.Conclusions: The present study revealed that conditional Itgav knockout and cilengitide treatment both significantly attenuated RIPF in mice by inhibiting alpha v integrin-mediated TGF beta 1 activation.