The role of contact system in septic shock: the next target? An overview of the current evidence

Nicola, Henrique

doi:10.1186/s40560-017-0228-x

Cited by 15 publications

(21 citation statements)

References 23 publications

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“…PK, which circulates in a noncovalent complex with HK 6 , cleaves HK and the proinflammatory peptide bradykinin is released 7 . In severe sepsis, activation of the contact system is archetypal 8 and multiple animal studies with different pharmacological interventions that inhibit FXII, bradykinin receptors or the interaction of contact factors with the bacterial surface 9 were done to evaluate potential therapeutic options 10 . However, surprisingly little is known about the precise role of contact factors during microbial sepsis.…”

Section: Introductionmentioning

confidence: 99%

The contact system proteases play disparate roles in streptococcal sepsis

et al. 2019

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Section: Introductionmentioning

confidence: 99%

The contact system proteases play disparate roles in streptococcal sepsis

et al. 2019

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“…We did not find any correlation between bradykinin and cardiovascular SOFA score, which calls into question a role of bradykinin in the maintenance of persisting failing circulation accompanying established sepsis. Our findings could thus explain the beneficial effect of bradykinin receptor antagonists when given within an hour after induction of experimental sepsis in animal models (33,34). This is opposed to the disappointing results found when evaluating the potent bradykinin-2 receptor (B 2 R) antagonist, deltibant, for treatment of sepsis in the clinical setting with a significant delay before initiation of treatment (32).…”

Section: Discussionmentioning

confidence: 88%

“…Since the presumably harmful effects of bradykinin could be targeted with pharmacological therapy , these observations ought to be verified in a general ICU population with sepsis caused by a wider array of pathogens. In the present clinical prospective matched observational study, we therefore tested the hypothesis that plasma levels of bradykinin are increased in patients with sepsis of a severity requiring intensive care.…”

mentioning

confidence: 99%

Early depletion of contact system in patients with sepsis: a prospective matched control observational study

Berkestedt

Andersson

Herwald

et al. 2018

APMIS

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Activation of the contact system generates bradykinin from high‐molecular‐weight kininogen and has been suggested to participate in the pathophysiology of sepsis. To test this, we prospectively measured bradykinin and high‐molecular‐weight kininogen levels in a cohort of sepsis patients requiring intensive care. From 29 patients meeting criteria for sepsis or septic shock according to Sepsis‐3, blood was sampled within 24 h and on the fourth day following admittance to intensive care. Patients planned for neurosurgery served as matched controls. Sequential organ failure assessment score and 90‐day mortality was registered. Bradykinin levels (median [interquartile range]) were lower in sepsis patients (79 [62–172] pg/ml) compared to controls (130 [86–255] pg/ml, p < 0.025) and did not correlate with mortality or severity of circulatory derangement. High‐molecular‐weight kininogen levels were lower in sepsis patients (1.6 [0.8–4.8] densitometry units) compared to controls (4.4 [2.9–7.7] densitometry units, p < 0.001), suggesting previous contact system activation. High‐molecular‐weight kininogen levels were lower in non‐survivors than survivors (p = 0.003) and negatively correlated to severity of circulatory derangement. We conclude that a role for bradykinin in later stages of severe sepsis must be challenged. Low high‐molecular‐weight kininogen concentrations suggest that the decrease in bradykinin is due to substrate depletion.

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“…Results from other studies on targeting the contact system in systemic infections (summarized in ) were not unambiguous: two rat models for sepsis showed that administration of soy bean trypsin inhibitor (SBTI, a PK antagonist), as well as a B1R antagonist, attenuated hypotension and mortality, respectively. Antagonism of B2R was therapeutic in a porcine sepsis model for Pseudomonas aeruginosa , but not for Neisseria meningiditis .…”

Section: Past and Present: The Contact System In Sepsismentioning

confidence: 98%

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

Hofman

Maat

Maas

2018

Journal of Thrombosis and Haemostasis

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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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The role of contact system in septic shock: the next target? An overview of the current evidence

Cited by 15 publications

References 23 publications

The contact system proteases play disparate roles in streptococcal sepsis

The contact system proteases play disparate roles in streptococcal sepsis

Early depletion of contact system in patients with sepsis: a prospective matched control observational study

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

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