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

Authors: Yu-wei Wang1, Yun-hao Wu1, Jia-zhi Zhang1, Jia-hui Tang1, Rui-ping Fan1, Fang Li1, Bo-yang Yu1, Jun-ping Kou1, Yuan-yuan Zhang1
1 State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
Correspondence to: Jun-ping Kou: junpingkou@cpu.edu.cn, Yuan-yuan Zhang: yuanyuanzhang@cpu.edu.cn,
DOI: 10.1038/s41401-020-00502-6
Received: 29 April 2020
Accepted: 31 July 2020
Advance online: 27 August 2020

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.
Keywords: ruscogenin; particulate matter; acute lung injury; bronchoalveolar lavage fluid; toll like receptor 4; endothelial permeability

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