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- Title
Tissue Kallikrein Exacerbating Sepsis-Induced Endothelial Hyperpermeability is Highly Predictive of Severity and Mortality in Sepsis.
- Authors
Ran, Xiao; Zhang, Qin; Li, Shaoping; Yu, Zhen; Wan, Li; Wu, Bin; Wu, Rongxue; Li, Shusheng
- Abstract
Aim: Sepsis, an acute, life-threatening dysregulated response to infection, affects practically all aspects of endothelial function. Tissue kallikrein (TK) is a key enzyme in the kallikrein–kinin system (KKS) which has been implicated in endothelial permeability. Thus, we aimed to establish a potentially novel association among TK, endothelial permeability, and sepsis demonstrated by clinical investigation and in vitro studies. Methods: We performed a clinical investigation with the participation of a total of 76 controls, 42 systemic inflammatory response syndrome (SIRS) patients, and 150 patients with sepsis, who were followed-up for 28 days. Circulating TK levels were measured with an enzyme-linked immunosorbent assay. Then, the effect of TK on sepsis-induced endothelial hyperpermeability was evaluated by in vitro study. Results: Data showed a gradual increase in TK level among controls and the patients with SIRS, sepsis, and septic shock (0.288± 0.097 mg/l vs 0.335± 0.149 vs 0.495± 0.170 vs 0.531± 0.188 mg/l, respectively, P < 0.001). Further analysis revealed that plasma TK level was positively associated with the severity and mortality of sepsis and negatively associated with event-free survival during 28 days of follow-up (relative risk, 3.333; 95% CI, 2.255– 4.925; p < 0.001). With a septic model of TK and kallistatin in vitro, we found that TK exacerbated sepsis-induced endothelial hyperpermeability by downregulating zonula occluden-1 (ZO-1) and vascular endothelial (VE)-cadherin, and these could be reversed by kallistatin, an inhibitor of TK. Conclusion: TK can be used in the diagnosis of sepsis and assessment of severity and prognosis of disease. Inhibition of TK may be a novel therapeutic target for sepsis through increasing ZO-1 and VE-cadherin, as well as downregulating endothelial permeability.
- Subjects
ENDOTHELIUM diseases; SEPSIS; SYSTEMIC inflammatory response syndrome; KALLIKREIN; SEPTIC shock; ENZYME-linked immunosorbent assay
- Publication
Journal of Inflammation Research, 2021, Vol 14, p3321
- ISSN
1178-7031
- Publication type
Article
- DOI
10.2147/JIR.S317874