High‐molecular‐weight kininogen: breaking bad in lethal endotoxemia

Abstract

To cite this article: Hofman ZLM, De Maat S, Maas C. High-molecular-weight kininogen: breaking bad in lethal endotoxemia. J Thromb Haemost 2018; 16: 193-5. Kinin formation is a powerful inflammatory process. In the intravascular compartment, bradykinin (RPPGFSPFR) is uniquely released from high-molecular-weight kininogen (HK) after activation of the plasma contact system (reviewed in [1]) and acts on its cognate kinin B2 receptor (B2R), which is constitutively expressed on endothelial cells. The action of carboxypeptidase N (which removes C-terminal arginines) converts bradykinin into des-Arg 9 -bradykinin. Active thrombin-activatable fibrinolysis inhibitor may exert a similar role during blood coagulation and bacterial infection. Des-Arg 9 -bradykinin is a potent agonist of kinin B1 receptor (B1R), which is expressed by endothelial cells and extravasated leukocytes at sites of inflammation. Altogether, both forms of bradykinin induce vascular leakage and mediate pain. Several kininases in plasma and tissue enzymatically degrade bradykinin to restrict its activity, thereby preventing widespread systemic vascular leakage and subsequent hypotension.Severe systemic bacterial infections (sepsis) are hallmarked by high activity of the (innate) immune and hemostatic system, in efforts to restrain and fight off invading pathogens. In particular, in the later and more dangerous phases of sepsis, mediators of the failing innate immune system cause damage to host tissues. A crucial feature of sepsis is a rapidly decreasing blood pressure (septic shock), caused by the systemic action of vasoactive mediators. With the increasing threat of multi-resistant infections, there is a dire need for increased mechanistic understanding, enabling development of new therapeutic approaches.Lipopolysaccharide (LPS), from the outer membrane of gram-negative bacteria is a notorious trigger of potent innate immune responses. Because of its amphipathic nature, LPS aggregates in a plasma environment. However, in order to elicit an innate immune response, it needs to be disaggregated into monomers. These monomers are recognized by LPS-binding protein (LBP), which presents them to CD14. Subsequently, signaling of the Toll-like receptor 4 (TLR4)-MD-2 complex leads to production of proinflammatory cytokines. However, whereas CD14, TLR4 and MD-2 are essential for LPS-induced mortality, LBP is not [2], suggesting the presence of other LPS-binding proteins. Over the past decade several proteins have been identified to bind LPS, but none proved essential for LPS-induced mortality. HK as playmaker in lethal endotoxemiaIn an exciting paper, Yang and colleagues provide new insights into the role of the contact system in mouse models of endotoxemia [3]. They show with compelling data, that HK is a major contributor to LPS-induced lethality. In an experimental model of lethal endotoxemia, by administration of LPS, wild-type (WT) mice generally succumb to the challenge between 10 and 50 h, as a result of multi-organ failure. In contrast, Kng À/À mice (...

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