Pediatric Critical Care Medicine:
Abstracts of the 7th World Congress on Pediatric Critical Care
1Paediatric Intensive Care Unit, Queensland Children’s Medical Research Institute, Brisbane, Australia 2University of Queensland, School of Biomedical Science, Brisbane, Australia 3Royal Brisbane Women’s Hospital, Burns Trauma & Critical Care Research Centre, Brisbane, Australia 4QIMR_Berghofer, Leukaemia Foundation of Queensland Laboratory, Brisbane, Australia
Background and aims: Vascular leak accompanies systemic inflammation (SIRS) causing hypotension and multiple organ failure.
Aims: We hypothesised that EphA2/ephrin-A1 signalling may be the link between cytokines released during inflammation and the vascular leak due to increased endothelial permeability in SIRS. We tested the effect of blocking EphA2/ephrin-A1 signalling in a mouse model of intestinal ischemia reperfusion injury (gut IR), which displays characteristics of SIRS.
Methods: C57BL/6J mice were administered EphA4-Fc (blocks EphA2-ephrinA1 receptor ligand interaction) 0.5 mg intraperitoneally (i.p.) [n=6] or Fc-control 0.5 mg i.p. [n=6]. Mice were anaesthetised 16 hours later and a CMA20 (100KDa, Global Scientific) microdialysis catheter, inserted in the subcutaneous skin of the back and perfused with electrolyte solution. Mice were subject to 30 minutes of superior mesenteric artery occlusion followed by reperfusion. Sham mice underwent laparotomy only. Total protein was measured in the microdialysate every 30 minutes as a marker of vascular leak. Local ethics approval was obtained.
Results: Gut IR induced systemic inflammation caused significant vascular leak measured by dialysate protein accumulation. Significantly, blockade of EphA2-ephrinA1 signalling with EphA4-Fc abolished vascular leak during reperfusion (P<0.05), compared with Fc-control treatment. Furthermore, histopathological injury scores of IR intestines were significantly reduced in EphA4-Fc treated mice.
Conclusions: We have proof-of-concept data that EphA2-ephrinA1 signalling mediates vascular leak in systemic inflammation and have identified a novel therapeutic strategy.