OSI-027 alleviates hyperoxia-induced lung injury in juvenile rats by inhibiting the mTOR signaling pathway

Abstract:

Objective：To investigate the inhibitory effect of the mammalian target of rapamycin（mTOR） 1/2 dual inhibitor OSI-027 on hyperoxia-induced lung injury and fibrosis in juvenile Sprague-Dawley（SD） rats. Methods：A total of 72 juvenile SD rats aged 3 weeks were randomly divided into air+normal saline group，hyperoxia+normal saline group，hyperoxia+rapamycin group，and hyperoxia+OSI-027 group，with 18 rats in each group. An animal model was established. Hyperoxia intervention was performed with 90% oxygen，and normal saline，rapamycin，and OSI-027 interventions were performed via intraperitoneal injection on days 1，3，6，8，10，and 13 of observation，respectively. On days 3，7，and 14，the change in body weight，lung wet/dry（W/D） ratio，lung injury scores，and alve－olar septal thickness were measured；lung histopathological ex－amination was performed；immunohistochemistry and Western blot were used to evaluate the distribution and expression of mTOR and phosphorylated ribosomal S6 kinase（pS6K1） in lung tissue. Results：As for the factor of time，there were significant increases over time in body weight（Ftime=297.098，P=0.000），immunohistochemistry of mTOR（Ftime=379.978，P=0.000），mTOR（Ftime=166.991，P=0.000），and pS6K1（Ftime=122.676，P=0.000）. All groups except the air+normal saline group had significant increases in lung injury scores（Ftime=1 410.362，P=0.000），alveolar septum thickness（Ftime=356.312，P=0.000），and pS6K1 immunohistochem－istry（Ftime=57.992，P=0.000） over time，as well as an increase in lung W/D ratio on days 3 and 7（Ftime=28.915，P=0.000） and a reduction in lung W/D ratio on day 14. As for the factor of grouping，the air+normal saline group had a significantly higher body weight（Fgroup=176.597，P=0.000） and significantly lower lung W/D ratio（Fgroup=28.484，P=0.000） and alveolar septum thickness（Fgroup=296.223，P=0.000） than the other groups. At all time points except day 3，the hyperoxia+normal saline group had significantly higher mTOR immunohistochemistry（Fgroup=134.100，P=0.000），pS6K1 immunohistochemistry（Fgroup=234.697，P=0.000），mTOR（Fgroup=59.377，P=0.000），and pS6K1（Fgroup=101.837，P=0.000） than the other groups；the hyperoxia+rapamycin group had significantly higher lung injury scores than the other groups（Fgroup=2 420.076，P=0.000），and the hyperoxia+OSI-027 group had significantly lower scores than the hyperox－ia+normal saline group and the hyperoxia+rapamycin group. Conclusion：A high concentration of oxygen can activate the mTOR sig－naling pathway in lung tissue；mTOR may promote the development and progression of hyperoxia-induced pulmonary fibrosis，possibly by inhibiting activation of the mTOR signaling pathway. OSI-027 can alleviate hyperoxia-induced lung injury and fibrosis in juvenile SD rats.