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Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells

Abstract

Idiopathic pulmonary fibrosis (IPF) is an aging‐associated disease with a poor prognosis. Emerging evidence has revealed that targeting senescent cells may be a potential treatment for IPF. In this study, we aimed to explore whether roxithromycin (RXM) can improve lung fibrosis by targeting senescent cells. First, we confirmed the ability of RXM to selectively kill senescent cells by inducing apoptosis and inhibiting the expression of senescence‐associated secretory phenotype (SASP) factors, suggesting the potential role of RXM as a “senolytic” and “senomorphic” drug. Next, we observed that TGF-β- and senescent cell-induced lung fibroblast activation was inhibited by RXM treatment, which prompted us to further investigate its effect in vivo. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, RXM was shown to attenuate lung injury, inflammation, and fibrosis. Furthermore, the senescent phenotype of lung tissues induced by BLM was significantly diminished after RXM administration, indicating the potential of RXM as an antifibrotic and antisenescent agent. Interestingly, NADPH oxidase 4 (NOX4), implicated in lung fibrosis and cell senescence, was shown to be inhibited by RXM treatments. The antifibroblast activation and antisenescent effects of RXM were abolished in NOX4 knockdown cells, demonstrating that RXM may ameliorate BLM-induced pulmonary fibrosis by targeting senescent cells mediated by the NOX4 pathway. Collectively, these data demonstrated that RXM may be a potential clinical agent for IPF and further supported the notion that targeting cellular senescence is a promising treatment for progressive age-related disease.

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Fig. 1: Roxithromycin selectively killed senescent cells.
Fig. 2: Roxithromycin inhibited the expression of SASP factors.
Fig. 3: Roxithromycin inhibited senescent cell-induced fibroblast activation.
Fig. 4: Roxithromycin attenuated bleomycin-induced lung injury and inflammation.
Fig. 5: Roxithromycin ameliorated bleomycin-induced pulmonary fibrosis.
Fig. 6: The bleomycin-induced cellular senescent phenotype was diminished by roxithromycin.
Fig. 7: Roxithromycin downregulated the expression of NOX4 in lung fibrosis.

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Acknowledgements

This work is supported by the National Science and Technology Major Project “Key New Drug Creation and Manufacturing Program” (2019ZX09201001-004-010, 2019ZX09201001-003-010), the National Natural Science Foundation of China (Grant U1703235, 31871414), the National Science Fund for Distinguished Young Scholars (Grant 81125023), and the K. C. Wong Education Foundation.

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XZ and YD designed and performed the experiments, analyzed the data, and wrote the paper; WCL and BXT contributed to the performance of experiments; JL and YZ initiated the project, planned and analyzed experiments, and supervised the research.

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Correspondence to Jia Li or Yi Zang.

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The authors declear no competing interests.

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Zhang, X., Dong, Y., Li, Wc. et al. Roxithromycin attenuates bleomycin-induced pulmonary fibrosis by targeting senescent cells. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00618-3

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Keywords

  • idiopathic pulmonary fibrosis
  • cellular senescence
  • roxithromycin
  • NOX4
  • senescence-associated secretory phenotype (SASP)

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