Tissue Kallikrein Exacerbating Sepsis-Induced Endothelial Hyperpermeability is Highly Predictive of Severity and Mortality in Sepsis

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.

Automated summary

This study revealed a significant association between TK levels and severity/mortality of sepsis, suggesting TK as a potential diagnostic and prognostic marker for sepsis. Inhibition of TK may serve as a novel therapeutic target for sepsis by regulating endothelial permeability.