Abstract
Objective
The systemic inflammatory response is regarded as the major cause of endotoxin-induced coagulopathy, which is a strong predictor of mortality in patients with severe sepsis. Simvastatin plays an important role in reducing inflammation. In addition, the gut has long been hypothesized to be the “motor” of critical illness, driving or aggravating sepsis by the increased intestinal permeability and bacterial translocation. Whether simvastatin plays a role in severe endotoxin-induced coagulopathy through the gut is unclear.
Methods
In this study, mice were administered 20 mg/kg simvastatin by gavage for 2 weeks and then intraperitoneally injected with 50 mg/kg endotoxin. Twelve h later, cytokine release, coagulation dysfunction, organ damage, and survival were assessed. Besides, the intestinal barrier, permeability, bacteria abundance, and translocation were evaluated.
Results
We found that the severity of endotoxin-induced coagulopathy was significantly improved in simvastatin-pretreated mice, who showed attenuated depletion of coagulation factors and platelets, decreased plasminogen activator inhibitor-1 (PAI-1) expression, reduced organ fibrin deposition, and improved survival time. Also, simvastatin reduced epithelial apoptosis and improved intestinal barrier function by upregulating antimicrobial peptides, lysozyme, and mucins. Simvastatin increased Lactobacillales counts, while the lipopolysaccharide group showed increased Desulfovibrio and Mucispirillum, which can produce harmful toxins. Finally, the decreased intestinal permeability in the simvastatin group caused reduced bacterial translocation in the organs and blood, both in terms of quantity and species.
Conclusion
Simvastatin improves the prognosis of severe endotoxemia, and the intestinal microenvironment participates in this process.
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Acknowledgements
The authors would like to thank all of the study participants and the Thrombosis and Hemostasis Laboratory of Hubei Province.
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The authors state that they have no conflicts of interest.
Author Heng MEI is a member of the Editorial Board for Current Medical Science. The paper was handled by the other editor and has undergone rigorous peer review process. Author Heng MEI was not involved in the journal’s review of, or decision related to, this manuscript.
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This study was supported by grants from the National Natural Science Foundation of China (No. 81873434) and the Natural Science Foundation of Hubei Province (No. 2020CFA065).
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Xu, M., Luo, Ll., Du, My. et al. Simvastatin Improves Outcomes of Endotoxin-induced Coagulopathy by Regulating Intestinal Microenvironment. CURR MED SCI 42, 26–38 (2022). https://doi.org/10.1007/s11596-022-2526-3
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DOI: https://doi.org/10.1007/s11596-022-2526-3