Ruscogenin attenuates particulate matter-induced acute lung injury in mice via protecting pulmonary endothelial barrier and inhibiting TLR4 signaling pathway

Abstract

The inhalation of particulate matter (PM) is closely related to respiratory damage, including acute lung injury (ALI), characterized by inflammatory fluid edema and disturbed alveolar-capillary permeability. Ruscogenin (RUS), the main active ingredient in the traditional Chinese medicine Ophiopogonis japonicus, has been found to exhibit anti-inflammatory activity and rescue LPS-induced ALI. In this study, we investigated whether and how RUS exerted therapeutic effects on PM-induced ALI. RUS (0.1, 0.3, 1 mg·kg−1·d−1) was orally administered to mice prior to or after intratracheal instillation of PM suspension (50 mg/kg). We showed that RUS administration either prior to or after PM challenge significantly attenuated PM-induced pathological injury, lung edema, vascular leakage and VE-cadherin expression in lung tissue. RUS administration significantly decreased the levels of cytokines IL-6 and IL-1β, as well as the levels of NO and MPO in both bronchoalveolar lavage fluid (BALF) and serum. RUS administration dose-dependently suppressed the phosphorylation of NF-κB p65 and the expression of TLR4 and MyD88 in lung tissue. Furthermore, TLR4 knockout partly diminished PM-induced lung injury, and abolished the protective effects of RUS in PM-instilled mice. In conclusion, RUS effectively alleviates PM-induced ALI probably by inhibition of vascular leakage and TLR4/MyD88 signaling. TLR4 might be crucial for PM to initiate pulmonary lesion and for RUS to exert efficacy against PM-induced lung injury.

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Fig. 1: RUS ameliorated PM-induced pulmonary pathological damage in mice.
Fig. 2: RUS protected the lung endothelial barrier from PM exposure in mice.
Fig. 3: RUS attenuated PM-triggered pulmonary inflammation in mice.
Fig. 4: RUS suppressed PM-induced activation of the TLR4/MyD88 signaling pathway in mice.
Fig. 5: RUS failed to ameliorate pulmonary edema and pathological damage induced by PM in TLR4-knockout mice.
Fig. 6: RUS failed to decrease vascular permeability and NF-κB p65 and MyD88 expression in TLR4-knockout mice.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81773971) and the Double First-Class University Project of China Pharmaceutical University (CPU2018GF07).

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YWW, JPK, and YYZ designed the project; YWW, YHW, JZZ, JHT, and RPF performed the experiments; YWW and YHW contributed to analyzing the data; YWW and RPF conducted the literature research; YWW organized the results and drafted the original manuscript; YWW, YHW, JPK, and YYZ reviewed and modified the manuscript; FL, BYY, JPK, and YYZ contributed to the funding acquisition.

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Correspondence to Jun-ping Kou or Yuan-yuan Zhang.

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Wang, Yw., Wu, Yh., Zhang, Jz. et al. Ruscogenin attenuates particulate matter-induced acute lung injury in mice via protecting pulmonary endothelial barrier and inhibiting TLR4 signaling pathway. Acta Pharmacol Sin (2020). https://doi.org/10.1038/s41401-020-00502-6

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Keywords

  • ruscogenin
  • particulate matter
  • acute lung injury
  • bronchoalveolar lavage fluid
  • toll like receptor 4
  • endothelial permeability

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