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Am J Physiol Gastrointest Liver Physiol 291: G885-G894, 2006. First published March 30, 2006; doi:10.1152/ajpgi.00380.2005
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HORMONES AND SIGNALING

Prostaglandin-mediated inhibition of Na+/H+ exchanger isoform 2 stimulates recovery of barrier function in ischemia-injured intestine

Adam J. Moeser,1 Prashant K. Nighot,2 Kathleen A. Ryan,1 Jenna G. Wooten,2 and Anthony T. Blikslager1

1Departments of Clinical Sciences and 2Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina

Submitted 22 March 2006 ; accepted in final form 27 April 2006

Prostaglandins stimulate repair of the ischemia-injured intestinal barrier in the porcine ileum through a mechanism involving cAMP-dependent Cl– secretion and inhibition of electroneutral Na+/H+ exchanger (NHE) activity. In the present study, we focused on the role of individual NHE isoforms in the recovery of barrier function. Ischemia-injured porcine ileal mucosa was mounted on Ussing chambers. Short-circuit current (Isc), transepithelial electrical resistance (TER), and isotopic fluxes of 22Na were measured in response to PGE2 and selective inhibitors of epithelial NHE isoforms. Immunoassays were used to assess the expression of NHE isoforms. Forty-five minutes of intestinal ischemia resulted in a 45% reduction in TER (P < 0.01). Near-complete restitution occurred within 60 min. Inhibition of NHE2 with HOE-694 (25 µM) added to the mucosal surface of the injured ileum stimulated significant elevations in TER, independent of changes in Isc and histological evidence of restitution. Pharmacological inhibition of NHE3 or NHE1 with mucosal S-3226 (20 µM) or serosal cariporide (25 µM), respectively, had no effect. Ischemia-injured tissues treated with mucosal S-3226 or HOE-694 exhibited equivalent reductions in mucosal-to-serosal fluxes of 22Na+ (by ~35%) compared with nontreated ischemia-injured control tissues (P < 0.05). Intestinal ischemia resulted in increased expression of the cytoplasmic NHE regulatory factor EBP50 in NHE2 but not in NHE3 immunoprecipitates. Selective inhibition of NHE2, and not NHE3, induces recovery of barrier function in the ischemia-injured intestine.

tight junction; restitution; Na+/H+ exchange


Address for reprint requests and other correspondence: A. T. Blikslager, College of Veterinary Medicine, North Carolina State Univ., 4700 Hillsborough St., Raleigh, NC 27606 (e-mail: Anthony_Blikslager{at}ncsu.edu)




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A. T. Blikslager, A. J. Moeser, J. L. Gookin, S. L. Jones, and J. Odle
Restoration of Barrier Function in Injured Intestinal Mucosa
Physiol Rev, April 1, 2007; 87(2): 545 - 564.
[Abstract] [Full Text] [PDF]


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