哺乳动物雷帕霉素靶蛋白（mTOR）信号通路对脂多糖所致急性肺损伤的影响
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摘要
背景：哺乳动物雷帕霉素靶蛋白(mTOR)是细胞内多种重要信号传导通路的枢纽,具有调节细胞的生存、增殖和凋亡等重要生理功能。目前越来越多的研究显示mTOR信号通路在炎症反应的起始和发展中也扮演了重要角色,但其在急性肺损伤(acute lung injury, ALI)中的作用尚不明确。
目的：建立气管内注射脂多糖(LPS)诱导小鼠急性肺损伤模型。明确ALI时mTOR活性的变化,应用雷帕霉素抑制mTOR活性,观察雷帕霉素对急性肺损伤的可能干预作用。
方法：应用单次气管内注入脂多糖(20mg／kg体重)的方法诱导小鼠急性肺损伤模型,并通过连续腹腔内注射雷帕霉素(Rapa,4mg/kg体重)5天来实现对小鼠ALI的干预。在气管内注射LPS 8小时后收集肺组织和灌洗液标本,通过观测小鼠的一般情况,肺部病理表现,肺泡灌洗液炎症细胞和炎症因子的表达,肺水肿的程度和ALI小鼠的生存预后等多项指标,来评价雷帕霉素对ALI的干预作用。
结果：肺组织中mTOR的下游蛋白pS6在LPS诱导的急性肺损伤模型中表达明显增强,而雷帕霉素的干预能够显著抑制pS6的过度活化。同时,雷帕霉素能够显著减少肺泡灌洗液中TNF-α(LPS vs LPS+Rapa:1672.74±193.73 vs 539.17±140.47pg/ml, P＜0.01)和IL-6 (LPS+Rapa vs LPS:1672.74±193.73pg/ml, P＜0.01)的表达水平；以及降低肺组织中IL-1β水平的上调(LPS vs LPS+Rapa:6394.20±904.59 vs 3196.08±487.46, pg/mg protein, P<0.01),增加了ALI时MMP-9的水平(LPS vs LPS+Rapa:17.98±3.17 vs 37.86±19.00, pg/mg protein, P<0.05)。但是,雷帕霉素不能改善ALI的严重程度。无论是中性粒细胞的浸润、还是肺水肿程度或病理的改变,雷帕霉素组和赋形剂组均无显著性差异。而且,雷帕霉素对ALI小鼠的生存预后也没有明显的干预作用。
结论：雷帕霉素能够抑制ALI时mTOR的过度活化,但对LPS诱导的ALI发生发展整个过程的干预作用甚微。本研究提示,单纯应用雷帕霉素抑制mTOR可能并不是ALI的潜在治疗方法。
Background:A growing body of evidence indicates that the mammalian target of rapamycin (mTOR) pathway, a key cellular signaling pathway associated with cellular functions, has distinct effects also in the in inflammatory process. However, the role of the mTOR pathway in lippolysaccharide (LPS) induced acute lung injury (ALI) is far of being elucidated. Objective:In this study, selective mTOR inhibitor rapamycin (Rapa) was used to test whether mTOR activation is critical in a murine model of LPS-induced ALI.
Methods:To examine the issue, mice were received LPS (20mg/kg) by intratracheal administration. Rapamycin-pretreated (8mg/kg body weight for consecutive five days) mice were compared to mice injected with vehicle alone. Lung tissues and bronchoalveolar lavage (BAL) were obtained 8 hours after LPS instillation. Levels of local inflammatory cytokines, cell numbers in BAL fluid, pulmonary edema, histopathology change, and ALI survival (40mg/kg LPS was used) were evaluated.
Results:The phosphorylation of S6, a major downstream target of mTOR, increased significantly in murine lung tissue after LPS stimulation compared to control, which was blocked by rapamycin. Administration of rapamycin diminished the levels of TNF-α(LPS vs LPS+Rapa:1672.74±193.73 vs 539.17±140.47 pg/ml,P<0.01)and IL-6 (LPS vs LPS+Rapa:7790.88±1170.54 vs 1968.57±474.62, pg/ml, P<0.01) in BAL fluid, and abrogated IL-1βup-regulation (LPS vs LPS+Rapa:6394.20±904.59 vs 3196.08±487.46, pg/mg protein, P<0.01) but reinforced MMP-9 up-regulation (LPS vs LPS+Rapa:17.98±3.17 vs 37.86±19,00, pg/mg protein, P<0.05) induced by LPS in lung tissue. However, rapamycin had little effects on the development and severity of lung injury after intratracheal LPS administration, as determined by pulmonary edema, inflammatory cell influx, and histopathology changes of ALI as well as the thickness of alveolar septum. And most important, there was no difference in lethality of LPS-mediated ALI between the rapamycin and vehicle pretreated mice.
Conclusion:These results indicate that inhibition of mTOR activation has a limited effect in ALI process. Our data indicated that rapamycin appears not be a candidate drug in treating ALI if it is used alone. Grant support:This work was supported by 973 Program of China (2009CB522106).
目的：建立气管内注射脂多糖(LPS)诱导小鼠急性肺损伤模型。明确ALI时mTOR活性的变化,应用雷帕霉素抑制mTOR活性,观察雷帕霉素对急性肺损伤的可能干预作用。
方法：应用单次气管内注入脂多糖(20mg／kg体重)的方法诱导小鼠急性肺损伤模型,并通过连续腹腔内注射雷帕霉素(Rapa,4mg/kg体重)5天来实现对小鼠ALI的干预。在气管内注射LPS 8小时后收集肺组织和灌洗液标本,通过观测小鼠的一般情况,肺部病理表现,肺泡灌洗液炎症细胞和炎症因子的表达,肺水肿的程度和ALI小鼠的生存预后等多项指标,来评价雷帕霉素对ALI的干预作用。
结果：肺组织中mTOR的下游蛋白pS6在LPS诱导的急性肺损伤模型中表达明显增强,而雷帕霉素的干预能够显著抑制pS6的过度活化。同时,雷帕霉素能够显著减少肺泡灌洗液中TNF-α(LPS vs LPS+Rapa:1672.74±193.73 vs 539.17±140.47pg/ml, P＜0.01)和IL-6 (LPS+Rapa vs LPS:1672.74±193.73pg/ml, P＜0.01)的表达水平；以及降低肺组织中IL-1β水平的上调(LPS vs LPS+Rapa:6394.20±904.59 vs 3196.08±487.46, pg/mg protein, P<0.01),增加了ALI时MMP-9的水平(LPS vs LPS+Rapa:17.98±3.17 vs 37.86±19.00, pg/mg protein, P<0.05)。但是,雷帕霉素不能改善ALI的严重程度。无论是中性粒细胞的浸润、还是肺水肿程度或病理的改变,雷帕霉素组和赋形剂组均无显著性差异。而且,雷帕霉素对ALI小鼠的生存预后也没有明显的干预作用。
结论：雷帕霉素能够抑制ALI时mTOR的过度活化,但对LPS诱导的ALI发生发展整个过程的干预作用甚微。本研究提示,单纯应用雷帕霉素抑制mTOR可能并不是ALI的潜在治疗方法。
Background:A growing body of evidence indicates that the mammalian target of rapamycin (mTOR) pathway, a key cellular signaling pathway associated with cellular functions, has distinct effects also in the in inflammatory process. However, the role of the mTOR pathway in lippolysaccharide (LPS) induced acute lung injury (ALI) is far of being elucidated. Objective:In this study, selective mTOR inhibitor rapamycin (Rapa) was used to test whether mTOR activation is critical in a murine model of LPS-induced ALI.
Methods:To examine the issue, mice were received LPS (20mg/kg) by intratracheal administration. Rapamycin-pretreated (8mg/kg body weight for consecutive five days) mice were compared to mice injected with vehicle alone. Lung tissues and bronchoalveolar lavage (BAL) were obtained 8 hours after LPS instillation. Levels of local inflammatory cytokines, cell numbers in BAL fluid, pulmonary edema, histopathology change, and ALI survival (40mg/kg LPS was used) were evaluated.
Results:The phosphorylation of S6, a major downstream target of mTOR, increased significantly in murine lung tissue after LPS stimulation compared to control, which was blocked by rapamycin. Administration of rapamycin diminished the levels of TNF-α(LPS vs LPS+Rapa:1672.74±193.73 vs 539.17±140.47 pg/ml,P<0.01)and IL-6 (LPS vs LPS+Rapa:7790.88±1170.54 vs 1968.57±474.62, pg/ml, P<0.01) in BAL fluid, and abrogated IL-1βup-regulation (LPS vs LPS+Rapa:6394.20±904.59 vs 3196.08±487.46, pg/mg protein, P<0.01) but reinforced MMP-9 up-regulation (LPS vs LPS+Rapa:17.98±3.17 vs 37.86±19,00, pg/mg protein, P<0.05) induced by LPS in lung tissue. However, rapamycin had little effects on the development and severity of lung injury after intratracheal LPS administration, as determined by pulmonary edema, inflammatory cell influx, and histopathology changes of ALI as well as the thickness of alveolar septum. And most important, there was no difference in lethality of LPS-mediated ALI between the rapamycin and vehicle pretreated mice.
Conclusion:These results indicate that inhibition of mTOR activation has a limited effect in ALI process. Our data indicated that rapamycin appears not be a candidate drug in treating ALI if it is used alone. Grant support:This work was supported by 973 Program of China (2009CB522106).
引文
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