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

article

Long, Li¹  Liang, Mulin²  Liu, Yanling⁴  Wang, Pan⁴  Dang, Hongxing⁴ 

[1] Health Management Center, The First Affiliated Hospital of Chongqing Medical University;Department of Neonatology, The Fifth Affiliated Hospital of Southern Medical University;Department of PICU, Children’s Hospital of Chongqing Medical University;Ministry of Education Key Laboratory of Child Development and Disorders;China International Science and Technology Cooperation Base of Child Development and Critical Disorders

关键词: Hyperoxia;    Lung injury;    Rapamycin;    OSI-027;    MTOR;   

DOI  :  10.1007/s13273-021-00131-y

来源: Korean Society of Toxicogenomics and Toxicoproteomics

【 摘 要 】

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.

【 授权许可】

Unknown