Inhibition of TGFβ1 activation prevents radiation-induced lung fibrosis

被引：12

作者：

Yi, Minxiao ^{[1
]}

Yuan, Ye ^{[2
]}

Ma, Li ^{[1
]}

Li, Long ^{[1
]}

Qin, Wan ^{[1
]}

Wu, Bili ^{[1
]}

Zheng, Bolong ^{[2
]}

Liao, Xin ^{[1
,3
]}

Hu, Guangyuan ^{[1
,4
]}

Liu, Bo ^{[1
,4
]}

机构：

[1] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Oncol, Wuhan, Peoples R China

[2] Huazhong Univ Sci & Technol, Sch Comp Sci & Technol, Wuhan, Peoples R China

[3] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Integrat Med, Wuhan, Peoples R China

[4] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Oncol, 1095 Jiefang Ave, Wuhan 430030, Hubei, Peoples R China

来源：

CLINICAL AND TRANSLATIONAL MEDICINE | 2024年 / 14卷 / 01期

基金：

中国国家自然科学基金;

关键词：

cilengitide; radiation-induced pulmonary fibrosis; transforming growth factor beta 1; alpha v integrin; PHARMACOLOGICAL INHIBITION; LATENT TGF-BETA-1; OPEN-LABEL; PHASE-II; CILENGITIDE; ALPHA-V-BETA-3; CANCER; GENE; BETA;

D O I：

10.1002/ctm2.1546

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：19

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