AIMS This study aimed to explore the possible mechanism of trauma-induced laryngotracheal stenosis and potential protective and therapeutic efficacy of quercetin on trauma-induced laryngotracheal stenosis. MAIN METHODS The expression and activity of fibrotic factors [interleukin (IL)-6, IL-8, autophagy related 5 (ATG5), collagen (COL)-1, tumor growth factor (TGF)-β COL-3, microtubule-associated proteins 1A/1B light chain 3A (LC3), and vascular endothelial growth factor (VEGF)] and fibrotic signaling mediators [mammalian target of rapamycin (mTOR) and phosphorylated AKT (pAKT)] were detected by real-time quantitative PCR (qRT-PCR), ELISA, Western blot, and immunohistochemical staining, respectively, in the lipopolysaccharide (LPS)-induced WI-38 (a human embryonic lung fibroblast cell line) cellular fibrotic model and a trauma-induced rabbit tracheal stenosis model, with and without quercetin treatment. KEY FINDINGS Pre-treatment with quercetin significantly reversed the LPS-induced upregulation of pro-fibrotic factors (IL-6, IL-8, COL-1, COL-3, LC3) and fibrotic signaling mediators (mTOR and AKT), and it induced the downregulation of ATG5 in the WI-38 cells. Furthermore, the anti-fibrotic activity of quercetin was confirmed in the trauma-induced rabbit tracheal stenosis model. Thus, the nasogastric administration of quercetin attenuated the tracheal stenosis of the rabbit tracheal stenosis model, in addition to effectively reversing an increase in pro-fibrotic factors (VEGF, IL-6, TGF-β, COL-1, and COL-3) and fibrotic signaling mediators (mTOR and AKT), as well as downregulating ATG5 of the rabbit tracheal stenosis model. SIGNIFICANCE Quercetin exhibits anti-fibrotic activity by inhibiting pro-fibrotic factors and AKT/mTOR signaling pathway, in addition to activating autophagy activity. This study provided experimental evidence supporting the application of quercetin in tracheal stenosis, clinically.

中文翻译：

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槲皮素的抗纤维化活性通过TGF-β/ AKT / mTOR信号通路减弱了兔气管狭窄。

目的本研究旨在探讨外伤性喉气管狭窄的可能机制以及槲皮素对外伤性喉气管狭窄的潜在保护和治疗作用。主要方法纤维化因子[白介素（IL）-6，IL-8，自噬相关5（ATG5），胶原（COL）-1，肿瘤生长因子（TGF）-βCOL-3，微管相关的表达和活性实时定量PCR（qRT--）检测蛋白1A / 1B轻链3A（LC3）和血管内皮生长因子（VEGF）和纤维化信号传导介质[雷帕霉素的哺乳动物靶标（mTOR）和磷酸化的AKT（pAKT）]。 PCR），ELISA，Western blot和免疫组化染色，脂多糖（LPS）诱导的WI-38（人类胚胎肺成纤维细胞系）细胞纤维化模型和创伤诱导的兔气管狭窄模型（有或没有槲皮素治疗）。主要发现用槲皮素预处理可显着逆转LPS诱导的促纤维化因子（IL-6，IL-8，COL-1，COL-3，LC3）和纤维化信号传导介质（mTOR和AKT）的上调，并且诱导WI-38细胞中ATG5的下调。此外，在创伤诱发的兔气管狭窄模型中证实了槲皮素的抗纤维化活性。因此，除了有效地逆转促纤维化因子（VEGF，IL-6，TGF-β，COL-1或其他）的升高外，在槲皮素的鼻胃给药还减轻了兔气管狭窄模型的气管狭窄。和COL-3）和纤维化信号传导介质（mTOR和AKT），以及下调兔气管狭窄模型的ATG5。重要性槲皮素除激活自噬活性外，还通过抑制促纤维化因子和AKT / mTOR信号传导途径而表现出抗纤维化活性。该研究提供了实验证据支持槲皮素在临床上在气管狭窄中的应用。