Abstract
BackgroundIn 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.MethodsExperimental, 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).ResultsB1R 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.ConclusionsB1R 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.
Highlights
In sepsis, the endothelial barrier becomes incompetent, with the leaking of plasma into interstitial tissues
This study investigates the effects in vivo of a Kinin B1 receptor (B1R) antagonist, the R-954, on septic hyperpermeability, VE-cadherin destabilization and survival in a later phase of polymicrobial sepsis in mice induced by cecal ligation and puncture (CLP)
Second experimental series: effect of B1R pharmacological blockade on VE‐cadherin expression We studied the role of sepsis in a potential VE-cadherin destabilization in an in vivo model, and the impact of a B1R antagonist on inflammatory parameters, organ dysfunctions and VE-cadherin maintenance in two organs of interest: lungs and kidneys (WT sham n = 7; wild-type strain C57BL/6J (WT) CLP n = 11; WT CLP R-954 n = 10)
Summary
The endothelial barrier becomes incompetent, with the leaking of plasma into interstitial tissues. 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 endothelium drives the host–pathogen responses by promoting inflammation, coagulation and vascular permeability, through activation of the contact-phase system and the kinin-kallikrein system When this response is uncontrolled, organ failures occur. Kinins, released at the early stage of sepsis, induce vascular leakage and vasodilation It acts at a later stage and elicits a sustained inflammatory response [4,5,6]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have