大黄酚通过mTOR/HIF-1α/VEGF信号通路对脂多糖诱导的急性肺损伤新生大鼠的保护作用

李震; 薛志华; 李玉梅; 杨俊艺; 王超

大黄酚通过mTOR/HIF-1α/VEGF信号通路对脂多糖诱导的急性肺损伤新生大鼠的保护作用

The role of chrysophanol against lipopolysaccharide-induced acute lung injury through mTOR/HIF-1α/VEGF signaling pathway in neonatal rats model

摘要

摘要:
目的： 探讨大黄酚通过mTOR/HIF-1α/VEGF信号通路对脂多糖诱导的新生大鼠急性肺损伤模型的影响。
方法： 腹腔注射脂多糖（LPS）制备急性肺损伤大鼠模型，大鼠分为6组：对照组、模型组、大黄酚2.5 mg/kg组、大黄酚5 mg/kg组、大黄酚10 mg/kg组和地塞米松5 mg/kg组，每组12只。干湿法检测肺组织湿/干（W/D）比；血气分析仪检查动脉氧分压（PaO₂）；肺功能检测仪检测用力肺活量（FVC）、0.3 s用力呼气容积（0.3 s FEV）、呼气峰值流速（PEF）、中期呼气流速（MEF）和平均肺动脉压力（mPAP）；HE染色检测肺组织病理损伤；ELISA试剂盒检测白细胞介素6（IL-6）、肿瘤坏死因子-α（TNF-α）和白细胞介素1β（IL-1β）水平；Masson染色检测肺纤维化；Western blotting检查TGF-β1、α-SMA、collagen Ⅰ、p-mTOR/mTOR、HIF-1α和VEGF蛋白表达。
结果： 与模型组相比较，大黄酚5、10 mg/kg组和地塞米松5 mg/kg组大鼠W/D降低（P ＜ 0.01），PaO₂水平升高（P ＜ 0.01），用力肺活量、0.3 s用力呼气容积、0.3 s FEV/FVC、呼气峰值流速和中期呼气流速升高（P ＜ 0.01），平均肺动脉压力降低（P ＜ 0.01），肺组织病理损伤明显改善，BALF中IL-6、TNF-α和IL-1β水平降低（P ＜ 0.01），肺纤维化水平明显改善，TGF-β1、α-SMA和collagen Ⅰ蛋白表达水平降低（P ＜ 0.01），p-mTOR/mTOR、HIF-1α和VEGF蛋白表达水平降低（P ＜ 0.01）。
结论： 大黄酚能改善LPS诱导的大鼠肺病理损伤、炎性反应和肺纤维化，可能与失活mTOR/HIF-1α/VEGF信号通路有关。

Abstract:
Objective To investigate the effect of chrysophanol on lipopolysaccharide (LPS)-induced acute lung injury in neonatal rats model through mTOR/HIF-1α/VEGF signaling pathway.
Methods The acute lung injury model in rats was established by intraperitoneal injection of LPS. The rats were divided into 6 groups randomly: control group, model group, chrysophanol at 2.5 mg/kg, 5 mg/kg, 10 mg/kg groups respectively and 5 mg/kg dexamethasone + model group, with 12 rats in each group. The ratio of wet/dry (W/D) of lung tissue was detected using wet-dry method, the arterial oxygen partial pressure (PaO₂) was detected by blood gas analyzer, the forced vital capacity (FVC), 0.3 s forced expiratory volume (0.3 s FEV), peak expiratory flow (PEF), middle expiratory flow (MEF) and mean pulmonary artery pressure (mPAP) were measured by pulmonary function analyzer, the pathological injury of lung tissue was detected by HE staining method; the levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were tested using ELISA kits; the changes of pulmonary fibrosis were detected by Masson staining method; the protein expression levels of TGF-β1, α-SMA, collagen Ⅰ, p-mTOR, mTOR, HIF-1α and VEGF were detected by Western blotting.
Results Compared with the model group, in the 5, 10 mg/kg chrysopherol groups and 5 mg/kg dexamethasone groups, the ratio of W/D was decreased (P ＜ 0.01), PaO₂ level was increased (P ＜ 0.01), FVC, 0.3 s FEV, 0.3 s FEV/FVC, PEF and MEF rate were increased (P ＜ 0.01), mPAP was decreased (P ＜ 0.01), the pathological injury of lung tissue was improved significantly (P ＜ 0.01), the levels of IL-6, TNF-α and IL-1β in BALF were reduced (P ＜ 0.01), the levels of pulmonary fibrosis were obviously improved (P ＜ 0.01), the protein expression levels of TGF-β1, α-SMA, collagen Ⅰ, p-mTOR/mTOR, HIF-1α and VEGF were decreased (P < 0.01).
Conclusions In LPS induced rats lung injury model, chrysophanol can improve lung pathological injury, inflammatory response and pulmonary fibrosis, which may be associated with the inactivation of mTOR/HIF-1α/VEGF signaling pathway.

HTML全文

参考文献(19)

施引文献

资源附件(0)