Ulinastatin

Systemic inflammation is involved in developing acute kidney injury (AKI) after cardiac surgery with cardiopulmonary bypass (CPB). Ulinastatin, a urinary trypsin inhibitor (UTI), has various anti-inflammatory effects. Our previous data displayed that UTI administration during CPB played a protective role in reducing the risk of AKI after cardiac surgery; however, its role in AKI pathogenesis remains unknown. In this study, UTI effectively decreased the expression levels of inflammatory factors, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and interleukin (IL)-18, in patients with CPB. Moreover, the proportion of patients with postoperative AKI decreased significantly. Experimental AKI was induced by 35 min of ischemia, followed by 48 h of reperfusion.The results showed that the preoperative administration of UTI reduced inflammatory cell infiltration and decreased the levels of pro-inflammatory cytokines, including IL-6, IL-18, and TNFα. Meanwhile, UTI inhibited apoptosis, reduced mitochondrial reactive oxygen species production. We further revealed that UTI could inhibit NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation by increasing the expression of nuclear factor-κB (IκB) kinase-alpha (IKKα) interacting with apoptosis-associated speck-like protein containing CARD (ASC) to alleviate kidney damage. These findings provide evidence of the renoprotective role of UTI in cardiac surgery-associated (CSA)-AKI, which is associated with the inhibition of NLRP3 inflammasome activation by upregulating IKKα.

Ulinastatin has beneficial effects in patients undergoing coronary artery bypass grafting (CABG) surgery due to its anti‐inflammatory properties, but the underlying mechanism remains unclear.

We used samples from patients undergoing CABG, a model of cardiac ischaemia–reperfusion injury (IRI) in mice and murine cardiac endothelial cell cultures to investigate links between ulinastatin, the kallikrein‐kinin system (KKS), endothelial dysfunction and cardiac inflammation in the response to ischaemia/reperfusion injury (IRI). These links were assessed using clinical investigations, in vitro and in vivo experiments and RNA sequencing analysis.

Ulinastatin inhibited the activity of tissue kallikrein, a key enzyme of the KKS, at 24 h after CABG surgery, which was verified in our murine cardiac ischaemia–reperfusion model. Under normal conditions, ulinastatin only inhibited kallikrein activity but did not affect bradykinin (B1/B2) receptors. Ulinastatin protected against IRI, in vivo and in vitro, by suppressing activation of the kallikrein‐kinin system and down‐regulating B1/B2 receptor‐related signalling pathways including ERK/ iNOS, which resulted in enhanced endothelial barrier function, mitigation of inflammation and oedema, decreased infarct size, improved cardiac function and decreased mortality. Inhibition of kallikrein and knockdown of B1, but not B2 receptors prevented ERK translocation into the nucleus, reducing reperfusion‐induced injury in murine cardiac endothelial cells.

Treatment with ulinastatin exerts a protective influence on cardiac reperfusion by suppressing activation of the kallikrein‐kinin system. Our findings highlight the potential of targeting kallikrein /bradykinin receptors to alleviate endothelial dysfunction, thus improving cardiac IRI.