Primary Motility  Disorders of the  Esophagus
 The Esophageal
 Mucosa
 The
 Esophagogastric  Junction
 Barrett's
 Esophagus

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OESO©2015
 
Volume: Barrett's Esophagus
Chapter: Screening and surveillance
 

What is the significance of persisting salivary epidermal growth factor output impairment in Barrett's patients with endoscopically healed mucosa?

C. Poplawski, M. Marcinkiewicz, T. Zbroch, J. Sarosiek (Kansas City)

The alimentary tract mucosa is exposed to a number of injurious exogenous agents ingested almost daily as components of food, drinks, or medication. Under this continuous challenge, the mucosal integrity is maintained both through the adequate prevention of injury and quick restitution (migration of existing cells from the margin of injury) accompanied by full reconstitution (remodeling) of the mucosal architecture after any even slightest mucosal damage [1-3].

The squamous esophageal mucosa is facing a unique challenge within the alimentary tract, as it is frequently exposed to injurious components of gastric and duodenal content, especially after the meal that promotes the gastroesophageal reflux (GER) or duodenogastroesophageal reflux resulting in gastroesophageal reflux disease (GERD).

Among protective mechanisms balancing the duodeno-gastroesophageal refluxate injurious potential, the pre-epithelial (the mucus-buffers layer covering the mucosa) and epithelial (protection at the cellular level) defenses are instrumental in promoting the health of the squamous epithelium [3].

Peptide growth factors, ubiquitous both within the pre-epithelial and epithelial mucosal compartments, seem to play a leading role in both prevention of injury and its repair. Peptide growth factor could be categorized as:
- mucosal integrity peptides (preserving mucosal integrity),
- or luminal surveillance peptides (acting at sites of an acute injury/repair), some of which could also be considered as rapid response peptides as quick onset of restitution or reconstitution could be pivotal in prevention of chronic injury and/or complications [1-5].

Among mucosal integrity peptides transforming growth factor a (TGFa) and pancreatic secretory trypsin inhibitor (PSTI) seem to play a leading role in prevention of mucosal injury. The luminal surveillance peptides group, on the other hand is well represented by epidermal growth factor (EGF). Both trefoil peptides, such as, TFF1 (previously known as pS2), TFF2 (also called spasmolytic polypeptide) and TFF3 (also known as intestinal trefoil factor) and EGF could also be considered as rapid response peptide [1-5].

It has been recently demonstrated that patients with endoscopic reflux esophagitis exhibit impairment in the rate of secretion of salivary and esophageal EGF and that this impairment persists after healing of endoscopic changes [6-8]. Therefore, patients with GERD who develop erosive reflux esophagitis as a result of an excessive mucosal exposure to injurious factors within the refluxate, are more likely to have impaired the abluminal mucosal surveillance process and diminished rapid mucosal response to injury due to inadequate content of EGF within the pre-epithelial defense [3]. In addition, in our preliminary data we have also demonstrated that patients with Barrett's esophagus, which develops in the setting of GERD, also exhibited an impairment in EGF secretion when compared to controls [9]. 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 [10].

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 1/3 of patients with reflux esophagitis 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.

It was recently demonstrated that the rate of the luminal release of TGFa in patients with reflux esophagitis was significantly higher than in controls both in basal conditions and during mucosal challenge with HCl/pepsin, mimicking the natural GER scenario [11]. In both controls and patients with reflux esophagitis luminal release of TGFa was significantly lower during mucosal exposure to HCl or HCl/Pepsin than corresponding basal values [11]. This may indicate that enhanced secretion of TGFa in reflux esophagitis may at least partly compensate for impairment in EGF secretion, although, most likely inadequate, since patients with reflux esophagitis are still more likely to develop Barrett's esophagus and its ultimate complication: adenocarcinoma.

In patients with Barrett's esophagus an increase in expression of TFGα or EGF/TGFα receptor with columnar epithelium has been demonstrated [12]. This increase was parallel to progression from nonspecialized to specialized intestinal epithelium and even was more profound in epithelium exhibiting dysplasia and adenocarcinoma [12]. No such dynamics in EGF expression was observed in the same specimens. These changes in growth factors and its receptor expression in patients with Barrett's esophagus were accompanied by increase in proliferating cell nuclear antigen (PCNA), Ki-67 antigen, ornithine decarboxylase activity and aneuploidy indicating enhanced cell proliferation, additionally augmented by p53 gene mutation [12, 13]. 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 [10, 14]. This hypothesis is supported by recently published data demonstrating esophageal squamous epithelial hyperplasia after chronic administration of EGF [15]. Deficiency of EGF hampers physiological functions of the esophageal squamous epithelium and leads to enhanced permeability of the esophageal mucosa to hydrogen ion [16, 17]. This in turn may accelerate damage to the esophageal epithelium accompanied 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. This in turn 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:
- the quantity and quality of duodeno-gastroesophageal refluxate,
- the intensity of esophageal propulsive primary and secondary peristalsis,
- the quantity and the quality of protective components within salivary secretion,
- the density and distribution of esophageal submucosal mucous glands and quality of their protective potential.

Since duodenal component of duodeno-gastroesophageal 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 [14, 18-21].

Patients with endoscopic reflux esophagitis also exhibit impairment in secretion of esophageal glycoconjugates (mucin) and PGE2 under the impact of luminal HCl/pepsin [22, 23]. This impairment may contribute to mucosal progression of mucosal injury under the influence of unbalanced aggressive power of the gastroesophageal refluxate. The rate of secretion of PSTI and trefoil peptides, so important in the maintenance of mucosal integrity and in rapid response to mucosal injury, in patients with reflux esophagitis with or without Barrett's esophagus remains to be explored.

References

1. Wong WM, Playford RJ, Wright NA. Peptide gene expression in gastrointestinal mucosal ulceration: ordered sequence or redundancy. Gut 2000;46:286-292.

2. Playford RJ, Boulton R, Ghatei MA, Bloom SR, Wright NA, Goodlad RA. Comparison of the effects of transforming growth factor alpha and epidermal growth factor on gastrointestinal proliferation and hormone release. Digestion 1996;57:362-367.

3. Sarosiek J, McCallum RW. The evolving appreciation of the role of esophageal mucosal protection in the pathophysiology of gastroesophageal reflux disease. J Pract Gastroenterol 1994;18:20J-20Q.

4. Playford RJ, Marchbank T, Chinery R, Evison R, Pignatelli M, Boulton RA, Thim L, Hanby AM. Human spasmolytic polypeptide is a cytoprotective agent that stimulates cell migration. Gastroenterology 1995;108:108-116.

5. Chinery R, Playford RJ. Combined intestinal trefoil factor and epidermal growth factor is prophylactic against indomethacin-induced gastric damage in the rat. Clin Sci 1995;88:401-403.

6. Rourk RM, Namiot Z, Sarosiek J, Yu Z, McCallum RW. Diminished content of esophageal epidermal growth factor in patients with reflux esophagitis. Am J Gastroenterol 1994;89:1177-1184.

7. Rourk RM, Namiot Z, Sarosiek J, Yu Z, McCallum RW. Impairment of salivary epidermal growth factor secretory response to esophageal mechanical and chemical stimulation in patients with reflux esophagitis. Am J Gastroenterol 1994;89:237-244.

8. Edmunds MC, Namiot Z, Sarosiek J, Rourk RM, Yu Z, McCallum RW. Esophageal epidermal growth factor impairment persists depite healing of endoscopic changes in patients with reflux esophagitis. Gastroenterology 1994;106:A73.

9. Sarosiek J, Edmunds MC, Namiot Z, Marcinkiewicz M, McCallum RW. Secretory profile of Barrett's esophagus in humans: its significantly modified protective potential. Gastroenterology 1994;106:A173.

10. Goetsch E. The structure of the mammalian esophagus. Am J Anat 1910;10:1-40.

11. Marcinkiewicz M, Sarosiek J, Edmunds ME, Namiot Z, McCallum RW. Detrimental impact of acid and pepsin on the rate of luminal release of transforming growth factor alpha: its potential pathogenetic role in the development of reflux esophagitis. J Clin Gastroenterol 1996;23:261-268.

12. Filipe MI, Jankowski J. Growth factors and oncogenes in Barrett's oesophagus and gastric metaplasia. Endoscopy 1993;25:637-641.

13. Fennerty MB, Sampliner RE, Garewal HS. Barrett's esophagus-cancer risk, biology and therapeutic management. Aliment Pharmacol Ther 1993;7:339-345.

14. Jankowski J, Murphy S, Coghill G, Grant A, Wormsley KG, Sanders DS, Kerr M, Hopwood D. Epidermal growth factor receptors in the oesophagus. Gut 1992;33:439-443.

15. Juhl CO, Jensen LS, Poulsen SS, Orntoft TF, Dajani EZ. Chronic treatment with epidermal growth factor causes esophageal epithelial hyperplasia in pigs and rats. Dig Dis Sci 1995;40:2717-2723.

16. Sarosiek J, Feng T, McCallum RW. The interrelationship between salivary epidermal growth factor and the functional integrity of the esophageal mucosal barrier in the rat. Am J Med Sci 1991;302:359-363.

17. Chen MC, Chang A, Buhl T, Soll AH. Apical EGF receptors regulate tight junctions and apical barrier function of gastric monolayers via cytochalasisn D-sensitive mechanisms. Proc AGA Symp Peptide Growth Factors GI Tract, Vail, CO, 1994;25.

18. Casson AG, Mukhopadhyay T, Cleary KR, Ro JY, Levin B, Roth JA. p53 gene mutations in Barrett's epithelium and esophageal cancer. Cancer Res 1993;51:4495-4499.

19. Jankowski J, Coghill G, Hopwood D, Wormsley KG. Oncogenes and onco-suppressor gene in adenocarcinoma of the oesophagus. Gut 1992;33:1033-1038.

20. Jankowski J, McMenemin R, Hopwood D, Penston J, Wormsley KG. Abnormal expression of growth regulatory factors in Barrett's oesophagus. Clin Sci 1991;81:663-668.

21. Jankowski J, McMenemin R, Yu C, Hopwood D, Wormsley KG. Proliferating cell nuclear antigen in oesophageal diseases; correlation with transforming growth factor alpha expression. Gut 1992;33:587-591.

22. Namiot Z, Sarosiek J, Marcinkiewicz M, Edmunds MC, McCallum RW. Declined human esophageal mucin secretion in patients with severe reflux esophagitis. Dig Dis Sci 1994;39:2523-2529.

23. Marcinkiewicz M, Sarosiek J, Edmunds MC, Scheurich J, Weiss P, McCallum RW. Monophasic luminal release of prostaglandin E2 in patients with reflux esophagitis under the impact of acid and acid/pepsin solutions:Its potential pathogenetic significance. J Clin Gastroenterol 1995;21:268-274.


Publication date: August 2003 OESO©2015