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Application of prostaglandin E2 improves ileal blood flow in NEC

      Abstract

      Purpose

      Indomethacin, a nonselective prostaglandin inhibitor used to treat patent ductus arteriosus, is associated with intestinal perforation inducing an NEC-like illness. We sought to define the contribution of prostaglandin E2 (PG E2) and its receptor EP4 to intestinal blood flow regulation in premature neonates with NEC.

      Methods

      Newborn Sprague-Dawley rats were randomized by litter to undergo experimental NEC induction or to serve as a CONTROL. At 48 hours of age, intestinal laser Doppler blood flow was assessed at baseline and after intraperitoneal administration of indomethacin, PG E2, EP4 antagonist, or EP4 agonist. Data were analyzed using a 2-way ANOVA with post hoc Tukey-Kramer correction.

      Results

      At baseline, NEC animals had lower intestinal blood flow than controls. Indomethacin, PG E2 and EP4 agonist all increased ileal blood flow, but PG E2 and EP4 agonist increased blood flow the most in NEC pups. EP4 antagonist decreased intestinal perfusion in both groups.

      Conclusion

      The above evidence suggests the importance of PG E2 and EP4 in regulation of neonatal intestinal blood flow. Since indomethacin treatment of patent ductus arteriosus in the premature infant is associated with an increased risk of intestinal perforation owing to compromised blood flow, PG E2 supplementation might provide intestinal protection if administered simultaneously with indomethacin.

      Key words

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      References

        • Grosfeld J.L.
        • Molinari F.
        • Chaet M.
        • et al.
        Gastrointestinal perforation and peritonitis in infants and children: experience with 179 cases over ten years.
        Surgery. 1996; 120: 650-655
        • Kabashima K.
        • Saji T.
        • Murata T.
        • et al.
        The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut.
        J Clin Invest. 2002; 109: 883-893
        • Downard C.D.
        • Grant S.N.
        • Matheson P.J.
        • et al.
        Altered intestinal microcirculation is the critical event in the development of necrotizing enterocolitis.
        J Pediatr Surg. 2011; 46: 1023-1028
        • Downard C.D.
        • Matheson P.J.
        • Shepherd J.A.
        • et al.
        Direct peritoneal resuscitation augments ileal blood flow in necrotizing enterocolitis via a novel mechanism.
        J Pediatr Surg. 2012; 47: 1128-1134
        • Maki A.C.
        • Matheson P.J.
        • Shepherd J.A.
        • et al.
        Intestinal microcirculatory flow alterations in necrotizing enterocolitis are improved by direct peritoneal resuscitation.
        Am Surg. 2012; 78: 803-807
        • Walker S.K.
        • Matheson P.J.
        • Schreiner M.T.
        • Smith J.W.
        • Garrison R.N.
        • Downard C.D.
        Intraperitoneal 1.5% Delflex improves intestinal blood flow in necrotizing enterocolitis.
        J Surg Res. 2013 Sep; 184: 358-364
        • O'Donovan D.J.
        • Baetiong A.
        • Adams K.
        • et al.
        Necrotizing enterocolitis and gastrointestinal complications after indomethacin therapy and surgical ligation in premature infants with patent ductus arteriosus.
        J Perinatol. 2003; 23: 286-290
        • Coombs R.C.
        • Morgan M.E.
        • Durbin G.M.
        • et al.
        Gut blood flow velocities in the newborn: effects of patent ductus arteriosus and parenteral indomethacin.
        Arch Dis Child. 1990; 65: 1067-1071
        • Chung D.H.
        • Ethridge R.T.
        • Kim S.
        • et al.
        Molecular mechanisms contributing to necrotizing enterocolitis.
        Ann Surg. 2001; 233: 835-842
        • Needleman P.
        • Turk J.
        • Jakschik B.A.
        • et al.
        Arachidonic acid metabolism.
        Ann Rev Biochem. 1986; 55: 69-102
        • Grishin A.
        • Wang J.
        • Hackam D.
        • et al.
        p38 MAP kinase mediates endotoxin-induced expression of cyclooxygenase-2 in enterocytes.
        Surgery. 2004; 136: 329-335
        • Ushikubi F.
        • Sugimoto Y.
        • Ichikawa A.
        • et al.
        Roles of prostanoids revealed from studies using mice lacking specific prostanoid receptors.
        Jpn J Pharmacol. 2000; 83: 279-285
        • Purdy K.E.
        • Arendshorst W.J.
        EP(1) and EP(4) receptors mediate prostaglandin E(2) actions in the microcirculation of rat kidney.
        Am J Physiol Renal Physiol. 2000; 279: F755-F764
        • Whittle B.J.
        Gastrointestinal effects of nonsteroidal anti-inflammatory drugs.
        Fundam Clin Pharmacol. 2003; 17: 301-313
        • Shimizu K.
        • Koga H.
        • Iida M.
        • et al.
        Microcirculatory changes in experimental mesenteric longitudinal ulcers of the small intestine in rats.
        Dig Dis Sci. 2007; 52: 3019-3028