Kinin B1 Receptor Inhibition With BI113823 Reduces Inflammatory Response, Mitigates Organ Injury, and Improves Survival Among Rats With Severe Sepsis

Murugesan, Priya; Jung, Birgit; Lee, Dongwon; Khang, Gilson; Doods, Henri; Wu, Dongmei

doi:10.1093/infdis/jiv426

Cited by 32 publications

(34 citation statements)

References 28 publications

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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 . 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 .…”

Section: Discussionmentioning

confidence: 83%

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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Section: Discussionmentioning

confidence: 83%

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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“…To assess the effect of rPPE18 on sepsis-induced organ damage, levels of serum ALT, a marker for liver damage, were determined (18,19,32). As expected, injection of 2.5 3 10 8 E. coli BL21 resulted in exacerbated liver injury as indicated by elevated serum ALT activity at 24 h postinfection.…”

Section: Resultsmentioning

confidence: 94%

“…Also, reduction in levels of TNF-a and overall inflammation correlates with increased survival in animal models of sepsis (13)(14)(15). Indeed, an exaggerated and dysregulated inflammatory response poses a challenge in sepsis and efforts need to be geared toward identifying effective anti-inflammatory agents which can reduce TNF-a and inflammation for successful resolution of sepsis (16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

Mycobacterium tuberculosis PPE18 Protein Reduces Inflammation and Increases Survival in Animal Model of Sepsis

Ahmed

Dolasia

Mukhopadhyay

2018

The Journal of Immunology

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PPE18 is a member of the PPE family. Previous studies have shown that recombinant PPE18 (rPPE18) protein binds to TLR2 and triggers a signaling cascade which reduces levels of TNF-α and IL-12, and increases IL-10 in macrophages. Because TNF-α is a major mediator of the pathophysiology of sepsis and blocking inflammation is a possible line of therapy in such circumstances, we tested the efficacy of rPPE18 in reducing symptoms of sepsis in a mouse model of induced septic peritonitis. rPPE18 significantly decreased levels of serum TNF-α, IL-1β, IL-6, and IL-12 and reduced organ damage in mice injected i.p. with high doses of Peritoneal cells isolated from rPPE18-treated mice had characteristics of M2 macrophages which are protective in excessive inflammation. Additionally, rPPE18 inhibited disseminated intravascular coagulation, which can cause organ damage resulting in death. rPPE18 was able to reduce sepsis-induced mortality when given prophylactically or therapeutically. Additionally, in a mouse model of cecal ligation and puncture-induced sepsis, rPPE18 reduced TNF-α, alanine transaminase, and creatinine, attenuated organ damage, prevented depletion of monocytes and lymphocytes, and improved survival. Our studies show that rPPE18 has potent anti-inflammatory properties and can serve as a novel therapeutic to control sepsis.

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“…This was consistent with two recent studies that used a B1R antagonist, BI113823, administered orally. This molecule attenuated lung injuries secondary to LPS or CLP [20,21]. In another model of acute lung injury caused by lipopolysaccharide inhalation, R-954 counteracts the role of B1R and prevented the airway hyperreactivity, the increased cellular infiltration and protein content in the bronchoalveolar lavage fluid, and inhibited the expression of cytokines/chemokines [22].…”

Section: Discussionmentioning

confidence: 99%

Kinin B1 receptor: a potential therapeutic target in sepsis-induced vascular hyperpermeability

et al. 2020

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Background: In sepsis, the endothelial barrier becomes incompetent, with the leaking of plasma into interstitial tissues. VE-cadherin, an adherens junction protein, is the gatekeeper of endothelial cohesion. Kinins, released during sepsis, induce vascular leakage and vasodilation. They act via two G-protein coupled receptors: B1 (B1R) and B2 (B2R). B1R is inducible in the presence of pro-inflammatory cytokines, endotoxins or after tissue injury. It acts at a later stage of sepsis and elicits a sustained inflammatory response. The aim of our study was to investigate the relationships between B1R and VE-cadherin destabilization in vivo in a later phase of sepsis. Methods: Experimental, prospective study in a university research laboratory. We used a polymicrobial model of septic shock by cecal ligation and puncture in C57BL6 male mice or C57BL6 male mice that received a specific B1R antagonist (R-954). We studied the influence of B1R on sepsis-induced vascular permeability 30 h after surgery for several organs, and VE-cadherin expression in the lung and kidneys by injecting R-954 just before surgery. The 96-h survival was determined in mice without treatment or in animals receiving R-954 as a "prophylactic" regimen (a subcutaneous injection of 200 µg/kg, prior to CLP and 24 h after CLP), or as a "curative" regimen (injection of 100 µg/kg at H6, H24 and H48 post-surgery). Results: B1R inactivation helps to maintain MAP above 65 mmHg but induces different permeability profiles depending on whether or not organ perfusion is autoregulated. In our model, VE-cadherin was destabilized in vivo during septic shock. At a late stage of sepsis, the B1R blockade reduced the VE-cadherin disruption by limiting eNOS activation. The survival rate for mice that received R-954 after sepsis induction was higher than in animals that received an antagonist as a prophylactic treatment. Conclusions: B1R antagonizing reduced mortality in our model of murine septic shock by limiting the vascular permeability induced by VE-cadherin destabilization through maintenance of the macrohemodynamics, consequently limiting organ dysfunctions.

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Kinin B1 Receptor Inhibition With BI113823 Reduces Inflammatory Response, Mitigates Organ Injury, and Improves Survival Among Rats With Severe Sepsis

Abstract: Administration of BI113823 reduced systemic and tissue inflammatory responses, prevented hemodynamic derangement, attenuated multiorgan injury, and improved overall survival.

Cited by 32 publications

References 28 publications

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

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

Mycobacterium tuberculosis PPE18 Protein Reduces Inflammation and Increases Survival in Animal Model of Sepsis

Kinin B1 receptor: a potential therapeutic target in sepsis-induced vascular hyperpermeability

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