Duodenal ulcer (DU) disease remains a major health problem in the USA (o.5 million new cases; 4 million recurrences; and a total cost of greater than 25 billion dollars/year). It has been shown that duodenal mucosal bicarbonate secretion (DMBS) in response to luminal acidification is deficient in Helicobacter pylori (HP) infected ulcer patients. This loss of bicarbonate secretion leads to mucosal damage and likely occurs due to as yet undefined bacterial and host factors. This proposal focuses on the host-defined pathophysiologic as well as cellular and subcellular duodenal transport processes in HP associated DU disease. Using the DU patient as a clinically relevant phenotype we intend to significantly advance our understanding of DMBS. The focus is on alterations in prostanoid-mediated human DMBS. It is hypothesized that H. pylori infection either through direct bacterial toxins, or from the resultant inflammatory changes alters the responsiveness of the duodenal epithelium to prostaglandins released in response to luminal acid. This mechanisms likely contributes to the defective acid- stimulated response seen in these patients, a major phenomenon in ulcer formation. Using novel in vitro methods the intent is to study biopsy tissue obtained from the HP-infected normal and DU patient and HP-noninfected normals and: (a) Define the HC03 secretory response of the duodenal epithelium to the major receptor mediated secretory pathways and their corresponding intracellular second messenger systems (PGE2-, STa-, carbachol-), (b) Assess the role of inflammation versus the direct bacterial effects of HP through sequential, timed in vitro studies on biopsies from the HP-infected DU patients (c) If PGE2- mediated events are the sole defect, with graded-dose response curves of HCO3 secretion establish that with PGE2 pretreatment, desensitization occurs in vitro to PGE2, and in vivo to luminal acid; (d) Confirm that desensitization is reversible with cyclooxygenase inhibition as well as H. pylori eradication; (e) Examine cAMP generation in duodenocytes in response to PGE2 in the 3 groups; (f) Use rt-PCR analysis to further study prostanoid receptor types in human duodenocytes and any alterations in the HP-infected DU patient and (f) Assess the effect of HP infection in vitro on the secretory function of normal duodenal epithelium.
| Sellers, Zachary M; Childs, Debbie; Chow, Jimmy Y C et al. (2005) Heat-stable enterotoxin of Escherichia coli stimulates a non-CFTR-mediated duodenal bicarbonate secretory pathway. Am J Physiol Gastrointest Liver Physiol 288:G654-63 |
| Rao, S P; Sellers, Z; Crombie, D L et al. (2004) A role for guanylate cyclase C in acid-stimulated duodenal mucosal bicarbonate secretion. Am J Physiol Gastrointest Liver Physiol 286:G95-G101 |
