The positive role of vitronectin in radiation induced lung toxicity: the in vitro and in vivo mechanism study

Abstract

BackgroundRadiation-induced lung toxicity (RILT) is a severe complication of radiotherapy in patients with thoracic tumors. Through proteomics, we have previously identified vitronectin (VTN) as a potential biomarker for patients with lung toxicity of grade ≥ 2 radiation. Herein, we explored the molecular mechanism of VTN in the process of RILT.MethodsIn this study, lentivirus encoding for VTN and VTN-specific siRNA were constructed and transfected into the cultured fibroblasts and C57BL mice. Real-time PCR, western blot and ELISA were used to examine expression of collagens and several potential proteins involved in lung fibrosis. Hematoxylin–eosin and immunohistochemical staining were used to assess the fibrosis scores of lung tissue from mice received irradiation.ResultsThe expression of VTN was up-regulated by irradiation. The change trend of collagens, TGF-β expression and p-ERK, p-AKT, and p-JNK expression levels were positively related with VTN mRNA level. Furthermore, overexpression of VTN significantly increased the expression level of α-SMA, as well as the degree of lung fibrosis in mice at 8 and 12 weeks post-irradiation. By contrast, siRNA VTN induced opposite results both in vitro and in vivo.ConclusionsVTN played a positive role in the lung fibrosis of RILT, possibly through modulation of fibrosis regulatory pathways and up-regulating the expression levels of fibrosis-related genes. Taken together, all the results suggested that VTN had a novel therapeutic potential for the treatment of RILT.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1474-y) contains supplementary material, which is available to authorized users.

Modulation of αVβ6 integrin in osteoarthritis-related synovitis and the interaction with VTN(381–397 a.a.) competing for TGF-β1 activation

“…Interestingly, this effect was observed at a concentration close to that found in plasma for pathological conditions. This result is consistent with previous findings proposing that VTN could exacerbate lung fibrosis through the upregulation of TGF-β1 signaling and the increase in α-SMA transcription 18 . Furthermore, it has already been proposed that TGF-β1 may induce myofibroblast differentiation by promoting differential interaction of integrins with ECM 58 and that, in pulmonary fibrosis, fibroblasts express increased uPAR, which augments the binding of integrins to ECM proteins 59 .…”

“…In a previous study, we found increased levels of a V65 vitronectin fragment, VTN (381–397 a.a.) , in the synovial fluid and serum of OA patients with respect to controls (healthy and RA subjects) 15 . VTN is an ECM protein that participates in cell migration, adhesion, and spreading 16 – 18 . This protein interacts with α V -containing integrins and specifically with α V β 3 integrin through its RGD motif 19 .…”

“…This protein interacts with α V -containing integrins and specifically with α V β 3 integrin through its RGD motif 19 . VTN also plays a positive role in fibrosis 18 , 20 , 21 . Interestingly, the fragment VTN (381–397 a.a.) is the result of VTN cleavage by plasmin, which affects the interaction of plasminogen activator inhibitor-1 (PAI-1) with VTN.…”

Urinary exosomal vitronectin predicts vesicoureteral reflux in patients with neurogenic bladders and spinal cord injuries

“…VTN, also known as S-protein, is one of the main components of the extracellular matrix that participates in cell spreading ( 33 ), cell adhesion ( 34 ) and cell migration ( 35 ). VTN is highly associated with various types of tissue fibrosis ( 36 , 37 ), including the fibrosis of kidney disease ( 38 ). More recently, a study focused on urine exosomal VTN revealed a positive relationship with renal fibrosis ( 39 ).…”

Promising Biomarkers of Radiation-Induced Lung Injury: A Review

“…It has been demonstrated that TGF-β enhances the expression of Insulin-like growth factor binding protein (IGFBP7), which further activates the ERK signaling pathway to promote EMT of AEC II [ 52 ]. Other molecules, such as αvβ6 integrin, ROS, and vitronectin (VTN), were also observed to be involved in fibrogenesis by promoting the expression of TGF-β [ 53 , 54 ]. In general, TGF-β displays wide regulatory effects on ECM formation, such as triggering the proliferation and differentiation of fibroblasts into myofibroblasts, overproduction of collagen and fibers in myofibroblasts, and inhibition of collagen degradation.…”