Background

The mechanism of long time and high-concentration oxygen treatment leading to acute lung injury (ALI) or developmental lung disease in infants is currently unclear. Here we found that compared with the effect of rapamycin, pan-mTOR1/2 inhibitor OSI-027, alleviates hyperoxia-induced lung injury (HILI) by modulation of mTORC2/AKT/TGF-β1 and mTORC1/4E-BP1 signaling in infant rats.

Objective

Infant rats were treated with continuous inhalation of 90% medical oxygen. Normal saline, rapamycin, or OSI-027 was intraperitoneally injected, and the status of lung injury was tested on days 3, 7, and 14. The activation of mTOR/AKT/TGFβ1 and mTORC1/4E-BP1 signaling was confirmed by immunohistochemistry and Western blot analysis in normal and hyperoxia-treated live precision-cut lung tissues. The inhibitory effect of OSI-027 extended to the active state of other proteins implicated in mTOR1/2 signaling was demonstrated in hyperoxia-induced injured lung tissues.

Results

Our data demonstrate that hyperoxia-induced serious lung inflammation and fibrosis. OSI-027 significantly attenuated the pathological process of HILI, inhibit the phosphorylation of the primary downstream targets of mTORC1/C2, and reduce the activation of TGF-β1 signaling.

Conclusions

The results suggest that mTORC2/AKT/TGF-β1 and the rapamycin-insensitive mTORC1/4E-BP1 (Thr37/46) signaling has an important effect during HILI with a potential meaning for the progress of novel anti-hyperoxia-injury strategies.

中文翻译：

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OSI-027通过调节高氧诱导的肺损伤幼鼠的mTORC2 / AKT /TGF-β1和mTORC1 / 4E-BP1信号传导减轻雷帕霉素不敏感

背景

目前尚不清楚长时间和高浓度氧气治疗导致婴儿急性肺损伤（ALI）或发育性肺部疾病的机制。在这里我们发现，与雷帕霉素的作用相比，pan-mTOR1 / 2抑制剂OSI-027通过调节mTORC2 / AKT /TGF-β1和mTORC1 / 4E-BP1信号转导减轻了高氧诱导的肺损伤（HILI）。 。

客观的

婴儿大鼠连续吸入90％的医用氧气。腹膜内注射生理盐水，雷帕霉素或OSI-027，并在第3、7和14天测试肺损伤的状态。免疫组织化学和免疫组化证实mTOR / AKT /TGFβ1和mTORC1 / 4E-BP1信号的激活。正常和高氧治疗的活体精密切割肺组织中的蛋白质印迹分析。在高氧诱导的受伤肺组织中证实了OSI-027的抑制作用扩展到了涉及mTOR1 / 2信号传导的其他蛋白质的活性状态。

结果

我们的数据表明高氧引起严重的肺部炎症和纤维化。OSI-027显着减弱了HILI的病理过程，抑制了mTORC1 / C2下游主要靶标的磷酸化，并降低了TGF-β1信号传导的激活。

结论

结果表明，mTORC2 / AKT /TGF-β1和雷帕霉素不敏感的mTORC1 / 4E-BP1（Thr37 / 46）信号传导在HILI期间具有重要作用，对新型抗高氧损伤策略的发展具有潜在意义。