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

Abstract

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.

• Authors: Stéphanie Ruiz, Fanny Vardon-Bounes, Marie Buléon, Céline Guilbeau-Frugier, Marie-Hélène Séguelas, Jean-Marie Conil, Jean-Pierre Girolami, Ivan Tack, Vincent Minville
• Journal: Journal of translational medicine (J Transl Med) Vol. 18 Issue 1 Pg. 174 (04 19 2020) ISSN: 1479-5876 [Electronic] England
• PMID: 32306971 (Publication Type: Journal Article)

Chemical References

• Kinins
• Receptor, Bradykinin B1
• Receptor, Bradykinin B2

Topics

• Animals
• Kinins
• Male
• Mice
• Prospective Studies
• Receptor, Bradykinin B1
• Receptor, Bradykinin B2
• Sepsis (complications, drug therapy)