The goal of this proposal is to determine mechanisms of alterations in electrolyte transport at the cellular level in chronic inflammatory bowel diseases. Diarrhea is a common and disabling symptom of diseases characterized by acute and chronic inflammation of the intestine. The pathophysiology of electrolyte transport at the cellular level is poorly understood in these conditions because of the multifactorial nature of fluid and electrolyte secretion in the chronically inflamed intestine, the complexity of the intact tissue preparations, the lack of good animal models and the inability to isolate viable epithelial cells suitable for the study of electrolyte transport. We have developed a technique to isolate crypt and villus cells from the normal rabbit ileum and most recently from the chronically inflamed rabbit ileum, which enable electrolyte transport to be studied in these individual cell types. In these cells coupled NaC1 absorption occurs by the dual operation of Na:H and C1:HC03 exchange on the brush border membrane (BBM), and HCO3 secretion may occur by stimulation of the BBM C1:HCO3 exchange or the basolateral (BLM) Na:H exchange. Therefore, we will determine whether a) immune-inflammatory mediators, b) cytokine and c) chronic inflammation inhibits NaC1 absorption by inhibition of the BBM Na:H and/or C1:HCO3 exchange of the villus cells and stimulates HCO3 secretion by stimulation of the BBM C1:HCO3 and/or the BLM Na:H exchange in crypt cells. Further we will also determine whether these changes correlate with change in intracellular 2nd messengers -- cAMP, cGMP and calcium. Better understanding of the pathophysiology of intestinal Na and C1 absorption and HCO3 secretion may ultimately result in the development of more efficacious treatment for inflammatory diarrheal diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First Independent Research Support & Transition (FIRST) Awards (R29)
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General Medicine A Subcommittee 2 (GMA)
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Hamilton, Frank A
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Ohio State University
Internal Medicine/Medicine
Schools of Medicine
United States
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Singh, Soudamani; Arthur, Subha; Talukder, Jamilur et al. (2015) Mast cell regulation of Na-glutamine co-transporters B0AT1 in villus and SN2 in crypt cells during chronic intestinal inflammation. BMC Gastroenterol 15:47
Saha, Prosenjit; Manoharan, Palanikumar; Arthur, Subha et al. (2015) Molecular mechanism of regulation of villus cell Na-K-ATPase in the chronically inflamed mammalian small intestine. Biochim Biophys Acta 1848:702-11
Manoharan, Palanikumar; Gayam, Swapna; Arthur, Subha et al. (2015) Chronic and selective inhibition of basolateral membrane Na-K-ATPase uniquely regulates brush border membrane Na absorption in intestinal epithelial cells. Am J Physiol Cell Physiol 308:C650-6
Arthur, Subha; Sundaram, Uma (2015) Inducible nitric oxide regulates intestinal glutamine assimilation during chronic intestinal inflammation. Nitric Oxide 44:98-104
Arthur, Subha; Coon, Steven; Kekuda, Ramesh et al. (2014) Regulation of sodium glucose co-transporter SGLT1 through altered glycosylation in the intestinal epithelial cells. Biochim Biophys Acta 1838:1208-14
Arthur, Subha; Sundaram, Uma (2014) Protein kinase C-mediated phosphorylation of RKIP regulates inhibition of Na-alanine cotransport by leukotriene D(4) in intestinal epithelial cells. Am J Physiol Cell Physiol 307:C1010-6
Saha, Prosenjit; Arthur, Subha; Kekuda, Ramesh et al. (2012) Na-glutamine co-transporters B(0)AT1 in villus and SN2 in crypts are differentially altered in chronically inflamed rabbit intestine. Biochim Biophys Acta 1818:434-42
Arthur, Subha; Saha, Prosenjit; Sundaram, Shanmuga et al. (2012) Regulation of sodium-glutamine cotransport in villus and crypt cells by glucocorticoids during chronic enteritis. Inflamm Bowel Dis 18:2149-57
Coon, Steven; Kekuda, Ramesh; Saha, Prosenjit et al. (2011) Reciprocal regulation of the primary sodium absorptive pathways in rat intestinal epithelial cells. Am J Physiol Cell Physiol 300:C496-505
Coon, Steven; Kekuda, Ramesh; Saha, Prosenjit et al. (2010) Glucocorticoids differentially regulate Na-bile acid cotransport in normal and chronically inflamed rabbit ileal villus cells. Am J Physiol Gastrointest Liver Physiol 298:G675-82

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