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

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 (I(sc)), 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 microM) added to the mucosal surface of the injured ileum stimulated significant elevations in TER, independent of changes in I(sc) and histological evidence of restitution. Pharmacological inhibition of NHE3 or NHE1 with mucosal S-3226 (20 microM) or serosal cariporide (25 microM), 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 approximately 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.

[1]  J. Pawlotsky,et al.  Effects of PGE2, misoprostol, and enprostil on guinea pig enterocyte adenylate cyclase , 1993, Digestive Diseases and Sciences.

[2]  M. Donowitz,et al.  Molecular physiology of intestinal Na+/H+ exchange. , 2005, Annual review of physiology.

[3]  L. Fliegel.  The Na+/H+ exchanger isoform 1. , 2005, The international journal of biochemistry & cell biology.

[4]  S. Shenolikar,et al.  Regulation of ion transport by the NHERF family of PDZ proteins. , 2004, Physiology.

[5]  Melissa M. Haskell,et al.  ClC-2 chloride secretion mediates prostaglandin-induced recovery of barrier function in ischemia-injured porcine ileum. , 2004, Gastroenterology.

[6]  R. Blaheta,et al.  The Na+/H+ exchange inhibitor HOE642 prevents stress-induced epithelial barrier dysfunction. , 2004, International journal of molecular medicine.

[7]  P. Dudeja,et al.  Differential regulation of Na+/H+ exchange isoform activities by enteropathogenic E. coli in human intestinal epithelial cells. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[8]  M. Manns,et al.  The Na+/H+ exchanger isoform 2 is the predominant NHE isoform in murine colonic crypts and its lack causes NHE3 upregulation. , 2004, American journal of physiology. Gastrointestinal and liver physiology.

[9]  S. Shenolikar,et al.  A C-terminal PDZ motif in NHE3 binds NHERF-1 and enhances cAMP inhibition of sodium-hydrogen exchange. , 2003, Biochemistry.

[10]  J. Galanko,et al.  PG-mediated closure of paracellular pathway and not restitution is the primary determinant of barrier recovery in acutely injured porcine ileum. , 2003, American journal of physiology. Gastrointestinal and liver physiology.

[11]  David García-Dorado,et al.  Pre-treatment with the Na+/H+ exchange inhibitor cariporide delays cell-to-cell electrical uncoupling during myocardial ischemia. , 2003, Cardiovascular research.

[12]  Michael Field,et al.  Intestinal ion transport and the pathophysiology of diarrhea. , 2003, The Journal of clinical investigation.

[13]  D. Little,et al.  PI3K signaling is required for prostaglandin-induced mucosal recovery in ischemia-injured porcine ileum. , 2003, American journal of physiology. Gastrointestinal and liver physiology.

[14]  J. Alverdy,et al.  Region-specific adaptation of apical Na/H exchangers after extensive proximal small bowel resection. , 2002, American journal of physiology. Gastrointestinal and liver physiology.

[15]  E. Chang,et al.  Metabolic acidosis in rats increases intestinal NHE2 and NHE3 expression and function. , 2002, American journal of physiology. Gastrointestinal and liver physiology.

[16]  G. Shull,et al.  Intestinal NaCl transport in NHE2 and NHE3 knockout mice. , 2002, American journal of physiology. Gastrointestinal and liver physiology.

[17]  M. Montrose,et al.  Apical Na+/H+ exchange near the base of mouse colonic crypts. , 2001, American journal of physiology. Cell physiology.

[18]  M. Miller,et al.  Loss of the NHE2 Na(+)/H(+) exchanger has no apparent effect on diarrheal state of NHE3-deficient mice. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[19]  J. Wade,et al.  Na+‐H+ exchanger 3 (NHE3) is present in lipid rafts in the rabbit ileal brush border: a role for rafts in trafficking and rapid stimulation of NHE3 , 2001, The Journal of physiology.

[20]  M. Cavet,et al.  Half-lives of plasma membrane Na(+)/H(+) exchangers NHE1-3: plasma membrane NHE2 has a rapid rate of degradation. , 2001, American journal of physiology. Cell physiology.

[21]  J. Turner,et al.  NHE3-dependent cytoplasmic alkalinization is triggered by Na(+)-glucose cotransport in intestinal epithelia. , 2001, American journal of physiology. Cell physiology.

[22]  A. Blikslager,et al.  PGE2 triggers recovery of transmucosal resistance via EP receptor cross talk in porcine ischemia-injured ileum. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[23]  A. Busch,et al.  NHE1-inhibitor cariporide prevents the transient reperfusion-induced shortening of the monophasic action potential after coronary ischemia in pigs , 2001, Basic Research in Cardiology.

[24]  M. Donowitz,et al.  Transepithelial resistance can be regulated by the intestinal brush-border Na(+)/H(+) exchanger NHE3. , 2000, American journal of physiology. Cell physiology.

[25]  R. Bohle,et al.  Na+/H+ Exchange Inhibitor Cariporide Attenuates Cell Injury Predominantly During Ischemia and Not at Onset of Reperfusion in Porcine Hearts With Low Residual Blood Flow , 2000, Circulation.

[26]  G. Boivin,et al.  Variant form of diffuse corporal gastritis in NHE2 knockout mice. , 2000, Comparative medicine.

[27]  S. Shenolikar,et al.  NHERF associations with sodium-hydrogen exchanger isoform 3 (NHE3) and ezrin are essential for cAMP-mediated phosphorylation and inhibition of NHE3. , 2000, Biochemistry.

[28]  Torben S. D. Johansen,et al.  NHE1, NHE2, and NHE3 contribute to regulation of intracellular pH in murine duodenal epithelial cells. , 2000, American journal of physiology. Gastrointestinal and liver physiology.

[29]  E. Chang,et al.  Regulation of Intestinal Epithelial Brush Border Na+/H+ Exchanger Isoforms, NHE2 and NHE3, in C2bbe Cells , 1999, The Journal of Membrane Biology.

[30]  S. Shenolikar,et al.  cAMP-induced Phosphorylation and Inhibition of Na+/H+ Exchanger 3 (NHE3) Are Dependent on the Presence but Not the Phosphorylation of NHE Regulatory Factor* , 1999, The Journal of Biological Chemistry.

[31]  M. Donowitz,et al.  NHE2 contains subdomains in the COOH terminus for growth factor and protein kinase regulation. , 1999, The American journal of physiology.

[32]  H. Thai,et al.  Effects of AT1 receptor blockade after myocardial infarct on myocardial fibrosis, stiffness, and contractility. , 1999, American journal of physiology. Heart and circulatory physiology.

[33]  R. Argenzio,et al.  Prostaglandin-induced recovery of barrier function in porcine ileum is triggered by chloride secretion. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[34]  E. Weinman,et al.  The Role of NHERF and E3KARP in the cAMP-mediated Inhibition of NHE3* , 1998, The Journal of Biological Chemistry.

[35]  G. Burckhardt,et al.  S3226, a novel inhibitor of Na+/H+ exchanger subtype 3 in various cell types , 1998, Pflügers Archiv.

[36]  G. Giebisch,et al.  Renal and intestinal absorptive defects in mice lacking the NHE3 Na +/H+ exchanger , 1998, Nature Genetics.

[37]  M. L. Calonge,et al.  In birds, NHE2 is major brush-border Na+/H+exchanger in colon and is increased by a low-NaCl diet. , 1998, American journal of physiology. Regulatory, integrative and comparative physiology.

[38]  Fermín Sánchez de Medina,et al.  Quantitative contribution of NHE2 and NHE3 to rabbit ileal brush-border Na+/H+exchange. , 1998, American journal of physiology. Cell physiology.

[39]  S. Shenolikar,et al.  The β2-adrenergic receptor interacts with the Na+/H+-exchanger regulatory factor to control Na+/H+ exchange , 1998, Nature.

[40]  G. Boivin,et al.  Targeted disruption of the murine Na+/H+ exchanger isoform 2 gene causes reduced viability of gastric parietal cells and loss of net acid secretion. , 1998, The Journal of clinical investigation.

[41]  J. M. Rhoads,et al.  Prostaglandins I2 and E2 have a synergistic role in rescuing epithelial barrier function in porcine ileum. , 1997, The Journal of clinical investigation.

[42]  R. Mrsny,et al.  Physiological regulation of epithelial tight junctions is associated with myosin light-chain phosphorylation. , 1997, The American journal of physiology.

[43]  J. Stechmiller,et al.  Gut dysfunction in critically ill patients: a review of the literature. , 1997, American journal of critical care : an official publication, American Association of Critical-Care Nurses.

[44]  M. Donowitz,et al.  cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[45]  M. Maher,et al.  The Na+/H+ exchange isoform NHE3 regulates basal canine ileal Na+ absorption in vivo. , 1997, Gastroenterology.

[46]  J. Waymack,et al.  Trauma, shock, and gut translocation. , 1996, New horizons.

[47]  M. Donowitz,et al.  Hyperosmolarity inhibits the Na+/H+ exchanger isoforms NHE2 and NHE3: an effect opposite to that on NHE1. , 1996, The American journal of physiology.

[48]  E. Deitch,et al.  Sepsis and multiple organ dysfunction syndrome: a clinical-mechanistic overview. , 1995, New horizons.

[49]  R. Argenzio,et al.  Prostanoids inhibit intestinal NaCl absorption in experimental porcine cryptosporidiosis. , 1993, Gastroenterology.

[50]  R. Argenzio,et al.  Endogenous prostanoids control ion transport across neonatal porcine ileum in vitro. , 1990, American journal of veterinary research.

[51]  C. Hawkey,et al.  Prostaglandins and the gastrointestinal mucosa: are they important in its function, disease, or treatment? , 1985, Gastroenterology.

[52]  J. Madara.  Increases in guinea pig small intestinal transepithelial resistance induced by osmotic loads are accompanied by rapid alterations in absorptive-cell tight-junction structure , 1983, The Journal of cell biology.