EGFR-p38 MAPK信号通路参与机械通气肺损伤大鼠肺组织HMGB1的表达

 目的：研究表皮生长因子受体(epidermal growth factor receptor, EGFR)-p38丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)信号通路在机械通气肺损伤(ventilator-induced lung injury, VILI)大鼠肺组织高迁移率族盒蛋白1 (high mobility group box 1 protein, HMGB1)表达中的作用。方法：健康SD大鼠32只随机分为4组：对照组（A组）不行机械通气，保留自主呼吸；小潮气量通气组（B组）潮气量(VT)为8 mL/kg；大潮气量通气组（C组）VT为40 mL/kg；大潮气量通气+EGFR拮抗剂AG-1478组为D组。机械通气4 h后处死动物，测定支气管肺泡灌洗液中总蛋白水平、白细胞计数以及肺湿干重比值(W/D)和髓过氧化物酶(MPO)活性，采用HE染色观察肺组织病理学改变，Western blotting方法检测肺组织磷酸化EGFR、磷酸化p38和HMGB1蛋白表达，RT-PCR方法检测EGFR mRNA的表达。结果：通气4 h后，与A组比较，C组肺组织病理学改变明显，总蛋白水平、白细胞计数、肺W/D、MPO活性、EGFR mRNA表达和磷酸化水平、p38磷酸化水平以及HMGB1蛋白表达均显著增加（P<0.05）；与C组比较，D组上述各项指标的变化均显著降低（P<0.05）。结论：大潮气量机械通气可引起大鼠急性肺损伤，其机制可能与通过EGFR-p38 MAPK信号通路介导HMGB1蛋白的表达有关。

EGFR-p38 MAPK signaling pathway is involved in expression of HMGB1 in pulmonary tissues of rats with ventilator-induced lung injury

AIM: To investigate the role of epidermal growth factor receptor (EGFR)-p38 mitogen-activated protein kinase (MAPK) pathway in the expression of high mobility group box 1 protein (HMGB1) in the lung tissues of rats with ventilator-induced lung injury (VILI).METHODS: Thirty-two healthy Sprague-Dawley (SD) rats were randomly divided into 4 groups (n=8 each): group A, spontaneous breathing; group B, small tidal volume ventilation (VT=8 mL/kg); group C, high tidal volume ventilation (VT=40 mL/kg); group D, high tidal volume ventilation plus EGFR antagonist AG-1478. The rats in group B, group C and group D were mechanically ventilated for 4 h and then all animals were sacrificed.Total protein content and white blood cell (WBC) count in bronchoalveolar lavage fluid (BALF), the lung wet/dry weight ratio (W/D) and myeloperoxidase (MPO) activity were determined. The histological changes of lung tissues were observed by HE staining. The EGFR protein and mRNA expression, p38 MAPK activity and HMGB1 protein expression in the lung tissues were also detected.RESULTS: The inflammatory responses as evidenced by lung HE staining, total protein and WBC in BALF, the lung W/D and MPO activity were significantly higher in group C than those in group A (P<0.05). The mRNA expression of EGFR, EGFR activity, p38 activity and HMGB1 protein level also significantly increased in group C (P<0.05) as compared with group A. Significant decreases in the above indexes in group D were observed as compared with group C.CONCLUSION:  High tidal volume ventilation induces acute lung injury, which may be related to up-regulation of HMGB1 expression through EGFR-p38 MAPK signal pathway.