The major long-term goal of this proposal is to understand the pathogenesis of the human disease, reflux esophagitis, and through this means, to open new avenues for its cure or prevention. The goal is approached mechanistically and from the relatively uncommon (even for esophagologists) vantage point of the target tissue, the esophageal mucosa. In this grant, therefore, we propose to: a) explore the mechanisms by which selected mucosal structures and functions contribute to esophageal defense against acid injury, b) explore the mechanisms by which luminal acid produces necrosis of esophageal epithelium, and c) determine whether a defect in human) esophageal mucosal structure-function contributes to the pathogenesis of reflux esophagitis. Specific studies include: 1) evaluation of the pre-epithelial (mucus-unstirred water layer- bicarbonate) defense in rabbit, opossum and human esophagus, including the magnitude of the lumen-to-surface pH gradient, contribution of the mucus layer and modulation of these parameters by exogenous agents. These evaluations are done by dark field microscopy for mucus thickness and extracellular pH microelectrodes for assessing the pH gradient; 2) characterization of the esophageal epithelial defense against acid injury in rabbit and human esophageal epithelium and mechanisms by which acid overcomes them to produce cell necrosis. Studies involving measurements of pHi are examined both in BCECF-loaded esophageal cells in primary culture using fluorescence microscopy and in esophageal cells impaled within intact epithelium by double-barreled pH sensitive intracellular microelectrodes. Studies on the mechanism of acid-induced cell swelling and necrosis are examined using a tissue weight-light microscopy methods or trypan blue exclusion techniques; 3) investigation of whether patients with reflux esophagitis have an epithelial (junctional) defect that causes or contributes to relapse of their disease. This is explored by comparing for reflux and on-reflux subjects the ability of their esophageal and oral (buccal) tissues in vivo to withstand an acid load as assessed by acid- induced change in esophageal and buccal potential difference, and by using light microscopy with histochemistry and transmission electron microscopy and freeze fracture to identify on esophageal biopsies the presence of dilated intercellular spaces and altered junctional morphology.
| 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 |
Showing the most recent 10 out of 48 publications
