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OSI-027 alleviates rapamycin insensitivity by modulation of mTORC2/AKT/TGF-β1 and mTORC1/4E-BP1 signaling in hyperoxia-induced lung injury infant rats
Molecular & Cellular Toxicology  (IF1.08),  Pub Date : 2021-04-01, DOI: 10.1007/s13273-021-00131-y
Li Long, Mulin Liang, Yanling Liu, Pan Wang, Hongxing Dang


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.


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.


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.


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.