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

Abstract

Xiao Ran,1 Qin Zhang,2 Shaoping Li,1 Zhen Yu,1 Li Wan,2 Bin Wu,3 Rongxue Wu,4 Shusheng Li1 1Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 2Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 3Laboratory of Platelet and Endothelium Biology, Department of Transfusion Medicine, Wuhan Hospital of Traditional Chinese and Western Medicine (Wuhan No.1 Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, People’s Republic of China; 4Department of Biological Sciences Division/Cardiology, University of Chicago, Chicago, IL, 60637, USACorrespondence: Qin Zhang Email [email protected] Li Email [email protected]: 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.Keywords: tissue kallikrein, sepsis, mortality, endothelial permeability, junction protein

Keywords

• tissue kallikrein
• sepsis
• mortality
• endothelial permeability
• junction protein