Sivelestat Alleviates Atherosclerosis by Improving Intestinal Barrier Function and Reducing Endotoxemia

Abstract

Emerging evidence suggests that atherosclerosis, one of the leading phenotypes of cardiovascular diseases, is a chronic inflammatory disease. During the atherosclerotic process, immune cells play critical roles in vascular inflammation and plaque formation. Meanwhile, gastrointestinal disorder is considered a risk factor in mediating the atherosclerotic process. The present study aimed to utilize sivelestat, a selective inhibitor of neutrophil elastase, to investigate its pharmacological benefits on atherosclerosis and disclose the gastrointestinal–vascular interaction. The activation of intestinal neutrophil was increased during atherosclerotic development in Western diet-fed ApoE-/- mice. Administration of sivelestat attenuated atherosclerotic phenotypes, including decreasing toxic lipid accumulation, vascular monocyte infiltration, and inflammatory cytokines. Sivelestat decreased intestinal permeability and endotoxemia in atherosclerotic mice. Mechanistically, sivelestat upregulated the expression of zonula occludens-1 in the atherosclerotic mice and recombinant neutrophil elastase protein-treated intestinal epithelial cells. Meanwhile, treatment of sivelestat suppressed the intestinal expression of inflammatory cytokines and NF-κB activity. In contrast, administration of lipopolysaccharides abolished the anti-atherosclerotic benefits of sivelestat in the Western diet-fed ApoE-/- mice. Further clinical correlation study showed that the circulating endotoxin level and intestinal neutrophil elastase activity were positively correlated with carotid intima-medial thickness in recruited subjects. In conclusion, sivelestat had pharmacological applications in protection against atherosclerosis, and intestinal homeostasis played one of the critical roles in atherosclerotic development.

Effect and safety of sivelestat on acute severe pancreatitis with systemic inflammatory response syndrome: A retrospective study

“…It is currently the only drug approved worldwide for the treatment of ALI/ARDS [20][21][22]. Recent studies have found that the powerful antiin ammatory ability of SV may also have a better inhibitory effect on the in ammatory response in other organs [23][24][25][26].…”

Calycosin improves atherosclerosis by reshaping the interaction between the gut microbiome and bile acid metabolism

“…Maintenance of homeostasis in the intestine is associated with factors such as the intestinal mucosal barrier, the internal environment, and its metabolites, in which the structure of the microbiota changes successively under conditions in which intestinal homeostasis is disrupted, and the gut microbiota and its metabolites can influence the intestinal barrier at all levels [25] . The beneficial bacteria can inhibit pathogenic bacteria reproduction, which can maintain gut microbiota homeostasis by increasing tight junction (TJ) protein content, prompting epithelial cell proliferation and differentiation, and promoting mucus and anti-inflammatory factor production, leaving the intestinal barrier intact and the inflammation level stable, which is beneficial for reducing the risk of diseases such as as as and its risk factors [26] . From the analysis of gut microbiota, calycosin was identified as an increase the diversity and richness of gut microbiota in AS mice compared with HFD group.…”

Neutrophil elastase aggravates periodontitis by disrupting gingival epithelial barrier via cleaving cell adhesion molecules

“…Nonetheless, the mechanism by which excessive neutrophils injure the gingival epithelial barrier is yet to be clarified. In addition, it was reported that NE inhibitor decreases endotoxemia by improving intestinal permeability and intestinal inflammatory response 33 ; however, the positive effect of NE inhibitor on periodontitis has rarely been reported. In this study, NE cleaved cell adhesion molecules and increased gingival epithelial cell monolayer permeability of periodontal pathogen in vitro.…”