The overall goals of this proposal are: a) to gain insight into the pathogenesis of reflux esophagitis and b) to establish alternative means (other than by acid inhibition) for its prevention and treatment.
The specific aims can be divided into 3 parts. The first part explores a novel mechanism for acid clearance by mammalian esophagus - that of esophageal bicarbonate (HCO3) secretion. Initially described in possums, the present studies will determine by ph-stat and ph-probe techniques whether he in vivo human esophagus, in health and reflux disease, secretes HCO3 and, if so, its capacity for acid clearance. The mechanisms of esophageal HCO3 secretion will also e explored using Ussing-chambered opossum mucosa and ph-stat technique. The second part tests the following hypothesis: luminal acid damages esophagus because H+ diffuse through the paracellular pathway then gain entry to the cell across the basolateral membrane on proteins normally used for regulation of intracellular pH (pHi). The hypothesis is tested by performing detailed studies of junctional morphology using electron microscopy with tracers, light microscopy with histochemical staining, and freeze fracture techniques and by studies of pHi regulatory processes in healthy and acid-exposed isolated cells (flourescent dye, BCECF, technique) and intact epithelium distribution of the weak acid, DMO, and 31P-NMR spectroscopy). The third part is to determine: a) the site and mechanisms of action of 3 groups of agents that protect the rabbit esophagus against acid damage without inhibiting acid secretion cytoprotection), and b) the capacity of these agents to prevent in experimental animals acid damage to gastric or duodenal epithelium and in humans acid damage to esophageal epithelium. Identification of mechanism/site of action will be carried out by the binding of radiolabelled CP agents to tissue. Tissues are then studied by utoradiography and SDS polyacrylamide gel electrophoresis, the latter to isolate proteins for production of antibodies for flourescein labelling. For studies of protection by CP agents, the change in resistance (and morphology) of acid-exposed Ussing-chambered epithelia from rabbit esophagus or duodenum will be assessed while protection of rat stomach against acid damage is assessed morphologically after in vivo gavage. Protection by Na 2SO4 is tested in the acid-perfused human esophagus in vivo by simultaneous measurements of esophageal potential difference.
| Bor-Caymaz, Canan; Bor, Serhat; Tobey, Nelia A et al. (2011) Effects of ethanol and extract of cigarette smoke on the rabbit buccal mucosa. J Oral Pathol Med 40:27-32 |
| Jovov, Biljana; Que, Jianwen; Tobey, Nelia A et al. (2011) Role of E-cadherin in the pathogenesis of gastroesophageal reflux disease. Am J Gastroenterol 106:1039-47 |
| Jovov, Biljana; Orlando, Geraldine S; Tobey, Nelia A et al. (2009) Ion transport and barrier function in a telomerase-immortalized human nondysplastic, Barrett's cell line (BAR-T). Dis Esophagus 22:386-95 |
| Atug, Ozlen; Dobrucali, Ahmet; Orlando, Roy Charles (2009) Critical pH level of lye (NaOH) for esophageal injury. Dig Dis Sci 54:980-7 |
| Orlando, Roy C (2008) Pathophysiology of gastroesophageal reflux disease. J Clin Gastroenterol 42:584-8 |
| Abdulnour-Nakhoul, Solange; Tobey, Nelia A; Nakhoul, Nazih L et al. (2008) The effect of tegaserod on esophageal submucosal glands bicarbonate and mucin secretion. Dig Dis Sci 53:2366-72 |
| Jovov, Biljana; Van Itallie, Christina M; Shaheen, Nicholas J et al. (2007) Claudin-18: a dominant tight junction protein in Barrett's esophagus and likely contributor to its acid resistance. Am J Physiol Gastrointest Liver Physiol 293:G1106-13 |
| Tobey, N A; Argote, C M; Awayda, M S et al. (2007) Effect of luminal acidity on the apical cation channel in rabbit esophageal epithelium. Am J Physiol Gastrointest Liver Physiol 292:G796-805 |
| Abdulnour-Nakhoul, Solange; Nakhoul, Nazih L; Wheeler, Scott A et al. (2005) HCO3- secretion in the esophageal submucosal glands. Am J Physiol Gastrointest Liver Physiol 288:G736-44 |
| Tobey, N A; Hosseini, S S; Argote, C M et al. (2004) Dilated intercellular spaces and shunt permeability in nonerosive acid-damaged esophageal epithelium. Am J Gastroenterol 99:13-22 |
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