KMID : 1034820210170030245
|
|
Molecular & Cellular Toxicology 2021 Volume.17 No. 3 p.245 ~ p.256
|
|
OSI-027 alleviates rapamycin insensitivity by modulation of mTORC2/AKT/TGF-¥â1 and mTORC1/4E-BP1 signaling in hyperoxia-induced lung injury infant rats
|
|
Long Li
Liang Mulin Liu Yanling Wang Pan Dang Hongxing
|
|
Abstract
|
|
|
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-¥â1 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/TGF¥â1 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-¥â1 signaling.
Conclusions: The results suggest that mTORC2/AKT/TGF-¥â1 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.
|
|
KEYWORD
|
|
Hyperoxia, Lung injury, Rapamycin, OSI-027, MTOR
|
|
FullTexts / Linksout information
|
|
|
|
Listed journal information
|
|
|
|