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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

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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-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.

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Acknowledgements

This study was supported by a Grant from the Basic And Frontier Research Project From Chongqing Science And Technology Commission, Chongqing, China (cstc2018jcyjAX0046).

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Author notes

  1. Li Long and Mulin Liang make equal contributions to this study.

Authors and Affiliations

  1. Health Management Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Li Long

  2. Department of Neonatology, The Fifth Affiliated Hospital of Southern Medical University, Guangzhou, 510900, China

    Mulin Liang

  3. Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, 400014, China

    Yanling Liu, Pan Wang & Hongxing Dang

  4. China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China

    Yanling Liu, Pan Wang & Hongxing Dang

  5. Department of PICU, Children’s Hospital of Chongqing Medical University, 136 Zhongshan No. 2 Road, Yu Zhong District, Chongqing, 400014, China

    Mulin Liang, Yanling Liu, Pan Wang & Hongxing Dang

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  1. Li Long
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  2. Mulin Liang
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Contributions

Conceptualization, writing-review, and editing: HD and LL; Data curation and investigation: LL and ML; Formal analysis, funding acquisition, methodology and software: HD, PW, LL, YL, ML; Writing-original draft: HD; Project administration: HD; Resources and visualization: LL, ML. Supervision: HD; Validation: LL and ML.

Corresponding author

Correspondence to Hongxing Dang.

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Conflict of interest

The authors have declared that no conflict of interest exists.

Ethical approval

All animal experiments were performed with local ethical committee approval (Ethics Committee of Chongqing Medical University, Chongqing, China). This study also followed the National Institutes of Health guide for the care and use of Laboratory Animals (NIH Publications No. 8023, revised 1978).

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Long, L., Liang, M., Liu, Y. et al. OSI-027 alleviates rapamycin insensitivity by modulation of mTORC2/AKT/TGF-β1 and mTORC1/4E-BP1 signaling in hyperoxia-induced lung injury infant rats. Mol. Cell. Toxicol. 17, 245–256 (2021). https://doi.org/10.1007/s13273-021-00131-y

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  • DOI: https://doi.org/10.1007/s13273-021-00131-y

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