Inhibition of TGFβ1 activation prevents radiation-induced lung fibrosis.
Inhibition of TGFβ1 activation prevents radiation-induced lung fibrosis.
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抑制tgf - β1激活可预防辐射诱导的肺纤维化。
DOI：
10.1002/ctm2.1546
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发表时间：
2024-01
影响因子：
10.6
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中科院分区：
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放射治疗是胸部肿瘤的主要治疗方式，但它可能引起肺纤维化。目前，辐射诱导肺纤维化（RIPF）的发病机制尚不清楚，缺乏有效的治疗方法。转化生长因子β1 （tgf - β1）在RIPF中起核心作用。我们发现，通过检测患者血清中活化tgf - β1和总tgf - β1水平，活化tgf - β1在放射性肺炎（RP）风险预测方面具有更好的效果。αv整合素在tgf - β1激活中起关键作用，但αv整合素介导的tgf - β1激活在RIPF中的作用尚不清楚。在这里，我们研究了αv整合素介导的tgf - β1激活在RIPF中的作用，以及整合素拮抗剂西仑吉肽在RIPF预防中的应用。ItgavloxP / loxP;Pdgfrb - Cre小鼠是通过有条件地敲除肌成纤维细胞中的Itgav而产生的，野生型小鼠用西伦吉肽或安慰剂治疗。所有小鼠均接受16 Gy的辐射或进行假辐射治疗。肺纤维化通过改良Ashcroft评分和微计算机断层扫描（CT）测量。采用酶联免疫吸附法（ELISA）检测血清tgf - β1浓度，Western blotting检测总Smad2/3和p - Smad2/3水平。条件敲除Itgav显著减弱RIPF （p < 0.01）。与对照组小鼠相比，基因敲除小鼠肺中的HUs减少（p < 0.001）。条件敲除Itgav可降低tgf - β1的活性分泌，抑制成纤维细胞p - Smad2/3的表达。外源性活性tgf - β1，而非潜伏性tgf - β1，逆转了这些减少。此外，西伦吉肽治疗也产生了类似的结果，并阻止了RIPF的发生。本研究表明，条件Itgav敲除和西伦吉肽处理均可通过抑制αv整合素介导的tgf - β1激活而显著减弱小鼠RIPF。活化的TGFβ1在预测放射性肺炎（RP）风险方面具有卓越的能力，并在辐射诱导肺纤维化（RIPF）的发展中起着至关重要的作用。肌成纤维细胞条件敲除Itgav可阻止小鼠发生RIPF。西伦吉肽通过抑制αv整合素介导的tgf - β1激活来缓解RIPF的发展，可能用于靶向预防RIPF的方法。活化的TGFβ1在预测放射性肺炎（RP）风险方面具有卓越的能力，并在辐射诱导肺纤维化（RIPF）的发展中起着至关重要的作用。在肌成纤维细胞中条件敲除Itgav可阻止小鼠产生RIPF。西伦吉肽通过抑制αv整合素介导的tgf - β1激活来缓解RIPF的发展，可能用于靶向预防RIPF的方法。
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 (TGFβ1) plays a central role in RIPF. We found that activated TGFβ1 had better performance for radiation pneumonitis (RP) risk prediction by detecting activated and total TGFβ1 levels in patient serum. αv integrin plays key roles in TGFβ1 activation, but the role of αv integrin‐mediated TGFβ1 activation in RIPF is unclear. Here, we investigated the role of αv integrin‐mediated TGFβ1 activation in RIPF and the application of the integrin antagonist cilengitide to prevent RIPF. ItgavloxP/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 TGFβ1 concentration, and total Smad2/3 and p‐Smad2/3 levels were determined via Western blotting. 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 TGFβ1 secretion and inhibited fibroblast p‐Smad2/3 expression. Exogenous active TGFβ1, but not latent TGFβ1, reversed these reductions. Furthermore, cilengitide treatment elicited similar results and prevented RIPF. The present study revealed that conditional Itgav knockout and cilengitide treatment both significantly attenuated RIPF in mice by inhibiting αv integrin‐mediated TGFβ1 activation. Activated TGFβ1 has a superior capacity in predicting radiation pneumonitis (RP) risk and plays a vital role in the development of radiation‐induced pulmonary fibrosis (RIPF). Conditional knock out Itgav in myofibroblasts prevented mice from developing RIPF. Cilengitide alleviated the development of RIPF by inhibiting αv integrin‐mediated TGFβ1 activation and may be used in targeted approaches for preventing RIPF. Activated TGFβ1 has a superior capacity in predicting radiation pneumonitis (RP) risk and plays a vital role in the development of radiation‐induced pulmonary fibrosis (RIPF). Conditional knocking‐out Itgav in myofibroblasts prevented mice from developing RIPF. Cilengitide alleviated the development of RIPF by inhibiting αv integrin‐mediated TGFβ1 activation and may be used in targeted approaches for RIPF prevention.