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.
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