Could lowering of salivary and esophageal epidermal growth factor in severe reflux esophagitis be related to the development of Barrett's mucosa?
M. Marcinkiewicz, J. Sarosiek, R.W. McCallum (Kansas City)
In our recent studies we have demonstrated that patients with endoscopic reflux esophagitis (RE) exhibit impairment in the rate of secretion of salivary and esophageal epidermal growth factor (EGF) and that this impairment persists after healing of endoscopic changes [1-3]. Patients with endoscopic RE also exhibit impairment in secretion of esophageal glycoconjugates (mucin) and PGE2 under the impact of luminal HCl/pepsin [4, 5]. All these factors contribute to mucosal protection and to balancing the aggressive power of gastroesophageal reflux (GER). In addition, in our preliminary data we have also demonstrated that patients with Barrett's esophagus (BE), which develops in the setting of gastroesophageal reflux disease (GERD), also exhibited an impairment in EGF secretion when compared to controls . This impairment in the rate of secretion of esophageal EGF could be attributed to lower expression of EGF gene at its peptide level within the esophageal submucosal mucous glands or to a lower number of submucosal mucous glands. A variation in the number of submucosal mucous glands in human esophagus from as low as 62 to as high as 741 glandular lobules has been reported by Goetsch .
A similar phenomenon of diminished expression of EGF peptide or a smaller size of salivary glands could also lead to decline of salivary EGF in both populations. Only approximately one third of patients with RE exhibited low EGF in both salivary and esophageal secretion, the remaining showed decline in salivary or esophageal secretion only. The clinical importance of this phenomenon of the most severe impairment in salivary and esophageal EGF secretion requires further investigation.
These data strongly suggest that although GER is prerequisite of the development of the esophageal mucosal pathology, the quality of mucosal protective mechanisms are significant and could be decisive in determining the development of complications.
In patients with BE an increase in expression of TGFa or EGF/TGFa receptor within columnar epithelium has been demonstrated . This increase was parallel to progression from nonspecialized to specialized intestinal epithelium and even was more profound in epithelium exhibiting dysplasia and adenocarcinoma . No such dynamics in EGF expression was observed in the same specimens.
These changes in growth factors and its receptor expression in patients with BE were accompanied by increase in proliferating cell nuclear antigen (PCNA), Ki-67 antigen, ornithine decarboxylase activity (ODC) and aneuploidy indicating enhanced cell proliferation, additionally augmented by p53 gene mutation [8, 9]. Therefore, metaplastic epithelium is acquiring its own source of peptide growth factor, predominantly TGFa binding to the same EGF receptor, which may serve as a source of high proliferative activity in metaplastic epithelium, may lead to uncontrolled growth in an autocrine fashion, and finally may promote the development of dysplastic changes and perhaps adenocarcinoma.
One may assume that the normal squamous epithelium, since it exhibits a high density of EGF receptor even on the apical cell membrane, requires a steady supply of EGF from salivary glands and esophageal submucosal mucous glands which also release their content into esophageal lumen through the ducts [7, 10]. This hypothesis is supported by recently published data demonstrating esophageal squamous epithelial hyperplasia after chronic administration of EGF .
Deficiency of EGF hampers physiological functions of the esophageal squamous epithelium and leads to enhanced permeability of the esophageal mucosa to hydrogen ion [12, 13]. Enhanced permeability of the esophageal mucosa to hydrogen ion may accelerate the damage and subsequent loss of the esophageal epithelium by apoptosis or cell necrosis, depending on pH changes within the intercellular milieu in the esophageal mucosa under the impact of GER, decreasing cell-cell adhesion and adhesion of squamous cells to basement membranes hampering their migratory and firm attachment potential.
Impairment of migration and attachment of squamous cells may promote migration of columnar cells which are phylogenetically well equipped, within their cytoskeleton network, with all molecules necessary to maintain their integrity under the impact of gastric or gastroduodenal milieu. This may explain the receding zone of squamous epithelium and expanding columnar compartment.
The borderline between these two distinct morphological compartment is probably determined by:
1) the quantity and quality of duodenogastroesophageal refluxate,
2) the intensity of esophageal propulsive primary and secondary peristalsis,
3) the quantity and the quality of protective components within salivary secretion,
4) the density and distribution of esophageal submucosal mucous glands and quality of their protective potential.
Since duodenal component of duodenogastroesophageal refluxate can be excessive, even the gastric type of metaplasia has to be supplemented or replaced by specialized intestinal epithelium which also undergoes further morphological and functional changes. This results in expression of nuclear oncogene c-myc, signal transduction oncogene ras, tumor suppressor gene rb, or fibroblast growth factor-related oncogenes hst-1 and int-2 and transformation to end point pathology manifested by the aggressive clone of transformed cells with a metastatic potential [10, 14-18].
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