Abstract
Acute lung injury (ALI) is a sudden onset systemic inflammatory response. ALI causes severe morbidity and death and currently no effective pharmacological therapies exist. Natural products represent an excellent resource for discovering new drugs. Screening anti-inflammatory compounds from the natural product bank may offer viable candidates for molecular-based therapies for ALI. In this study, 165 natural compounds were screened for anti-inflammatory activity in lipopolysaccharide (LPS)-challenged macrophages. Among the screened compounds, flavokawain B (FKB) significantly reduced LPS-induced pro-inflammatory IL-6 secretion in macrophages. FKB also reduced the formation of LPS/TLR4/MD2 complex by competitively binding to MD2, suppressing downstream MAPK and NF-κB signaling activation. Finally, FKB treatment of mice reduced LPS-induced lung injury, systemic and local inflammatory cytokine production, and macrophage infiltration in lungs. These protective activities manifested as increased survival in the ALI model, and reduced mortality upon bacterial infection. In summary, we demonstrate that the natural product FKB protects against LPS-induced lung injury and sepsis by interacting with MD2 and inhibiting inflammatory responses. FKB may potentially serve as a therapeutic option for the treatment of ALI.
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Acknowledgements
Financial support was provided by the National Natural Science Foundation of China (81970338 to YW, 82070833 to CZ, and 82000793 to WL), Natural Science Foundation of Zhejiang Province (LR18H160003 to YW), and Zhejiang Provincial Key Research and Development Program (2021C03070 to CZ).
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WL, LBY, CCQ, BM, GMM, XMM, JW, CHH, BJ, and LXZ: collection, analysis, and interpretation of data; YW, CZ, and GL: conception and design, interpretation of data, manuscript writing, and manuscript revision.
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Luo, W., Yang, Lb., Qian, Cc. et al. Flavokawain B alleviates LPS-induced acute lung injury via targeting myeloid differentiation factor 2. Acta Pharmacol Sin 43, 1758–1768 (2022). https://doi.org/10.1038/s41401-021-00792-4
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DOI: https://doi.org/10.1038/s41401-021-00792-4
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