Abstract
The pharmacotherapeutic mechanism of colchicine, a tricyclic, lipid-soluble alkaloid extracted from the plant of the Lily family Colchicum autumnale, has not been fully understood in diverse disorders, including sepsis-induced acute lung injury (ALI). The study aimed at exploring the impact of colchicine on sepsis-induced ALI and the relevant mechanisms. Colchicine significantly attenuated ALI in mice caused by sepsis by alleviating respiratory dysfunction and pulmonary edema in mice, inhibiting NLRP3 inflammasome formation, and reducing oxidative stress, pyroptosis, and apoptosis of murine alveolar macrophage (J774A.1) cells. The targets of colchicine were predicted in the superPRED database and intersected with the differentially expressed genes in the GSE5883 and GSE129775 datasets. The major targets were subjected to protein–protein interaction network generation and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. It was thus found that colchicine inhibited STAT3 phosphorylation but did not alter STAT3 total protein expression. Phosphorylated STAT3 recruited EP300 to form a complex to promote histone H3 acetylation and histone H4 acetylation of NLRP3 promoter, leading to pyroptosis of J774A.1 cells. In conclusion, inhibition of STAT3 phosphorylation by colchicine represses NLRP3 promoter acetylation via the STAT3/EP300 complex, thereby alleviating ALI caused by sepsis.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Acknowledgements
Thanks to Haitao Li, Yan Zhang, Yanhui Cui, Chao Song, Fengyu Lin, and Yi Li for their constructive suggestions and help to the author in the process of experiment and manuscript writing.
Funding
This work was supported by the National Natural Science Foundation of China (No. 81770080); the Xiangya Hospital-Beida Weiming Clinical Rehabilitation Research Fund (No. XYWM2015I20); the Ministry of Science and Technology of the People’s Republic of China (No. 2016YFC1304204); Peking Union Medical Foundation—Ruiyi Emergency Medical Research Fund (No. R2021004) and Hainan Provincial Medical and Health Research Project (No. 20A200340).
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YSL Contributed to the conception and design of the work, drafted the manuscript, and performed most of the experiments. HY, FZ, YHOY, and PHP Contributed to analyzing data, revising the manuscript critically, and performing some of the experiments. All authors have read and approved the final manuscript.
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Liu, Y., Yang, H., Zhu, F. et al. Inhibition of STAT3 phosphorylation by colchicine regulates NLRP3 activation to alleviate sepsis-induced acute lung injury. Inflammopharmacol 31, 2007–2021 (2023). https://doi.org/10.1007/s10787-023-01199-9
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DOI: https://doi.org/10.1007/s10787-023-01199-9