P268: Urocortins govern microvascular permeabilty during inflammation

Abstract

Introduction: Urocortins (Ucns) are known to regulate vascular tone and more recently have been implicated in mediating intestinal inflammation. Our hypothesis is that Ucn1 promotes microvascular permeability and this effect is exacerbated during systemic inflammation. The purposes of this study are: 1) to determine the effect of Ucn1 on microvascular permeability, and 2) to determine the effect of Ucn1 on microvascular permeability during inflammation. Methods: First, basal microvascular permeability (Lp) of rat mesenteric post-capillary venules was measured using an in vivo micro-cannulation technique for 50 minutes (control 1). Second, the effect of Ucn1 on microvascular permeability (Lp-Ucn1) was obtained by continuous perfusion of 10-7M Ucn1; Lp-Ucn1 was recorded at 10 min intervals for 50 min. Third, a bolus of lipopolysaccharide (LPS, 10mg/kg) into the rat femoral vein was used to induce inflammation. The effect of LPS on Lp was measured for 50 min (control 2). Fourth, to examine if Ucn1 exacerbated the effects of LPS-induced changes in Lp, 10mg/kg LPS and 10-7M Ucn1 were continuously perfused in post capillary venules and changes in Lp were measured at 10 min intervals for 50 min. Results: Ucn1 alone increased Lp 2-fold over baseline with a peak effect at 30 min (Lp baseline = 0.96 ± 0.03, Lp Ucn1 = 2.02 ± 0.20) (p = 0.005). LPS-induced inflammation also increased Lp 2-fold over baseline (Lp baseline = 0.92 ± 0.04, Lp-LPS= 1.93 ± 0.14) (p = 0.005). Surprisingly, Ucn1 perfusion increased Lp 3-fold (Lp = 6.42 ± 0.23) within 2 minutes of administration and exhibited a maximum effect of a 5-fold increase in Lp at 20 minutes (Lp = 9.87 ± 0.14) (p = 0.001). Conclusion: Ucn1 increases microvascular fluid leak. Ucn1 acts synergistically with LPS to increase microvascular fluid losses during inflammation. Thus, Ucn1 acts as a key inflammatory mediator in endotoxic shock in the gut.