What is the value of the mucosal content of prostaglandin E2, epidermal growth factor and transforming growth factor a in the surveillance of Barrett's patients?

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

Barrett's esophagus results from a relentless exposure of the esophageal squamous epithelium to components of gastroesophageal reflux (GER) and subsequent chronic mucosal injury/repair phenomenon leading to differentiation of the stem (progenitor) cell into the columnar epithelial phenotype. The development of the gastric type columnar epithelium within the esophageal mucosa in the early phase of Barrett's esophagus represents an adaptive mechanism intended to balance acidic and proteolytically active milieu of GER, highly injurious to the squamous epithelium.

The fact that Barrett's esophagus undergoes further evolution from the gastric type of columnar epithelium towards the specialized intestinal mucosa clearly indicates that factors, other than acid and pepsin, originating from the duodenal lumen during duodenogastroesophageal reflux (DGER) participate as well. The specialized intestinal epithelium is well developed to resist the injury by bile components. However, since the ratios between acid, pepsin and bile acids is continuously changing throughout the periods of fasting and subsequent ingestion of meals, GER episodes exhibiting predominantly acid/pepsin milieu will still be detrimental to the integrity of the specialized intestinal epithelium. Since each day the specialized intestinal metaplasia is simultaneously exposed to components of both gastric and duodenal contents, this results in persisting injury/repair phenomenon inevitably leading to chronic inflammation and progressive phenotypic changes with development of low-grade dysplasia (LGD), high-grade dysplasia (HGD) and ultimately esophageal adenocarcinoma. Thus, as an ultimate goal in ideal treatment strategy emphasis should be placed on elimination of both GER and DGER.

Since aggressive factors within the GER or DGER always operate at the luminal side of the mucosal compartment, pre-epithelial defense becomes the vanguard of mucosal protection. Pre-epithelial mucosal defense exists as a mucus-buffer layer covering the esophageal mucosa in humans and is designated to absorb the major brunt of the injurious effects of the acid-pepsin-bile acids triad. The thickness of mucus-buffer layer is approximately 95 ± 12µm [1]. This mucus-buffer layer is capable to withstand the pH gradient from acidic on its luminal side (2.18 ± 0.11) to significantly less acidic (4.08 ± 0.41; P < 0.02) at its apical cell membrane perimeter [2]. This pH gradient is less potent than that recorded in the human gastric mucosa but stronger than that present within the duodenal mucosa [2].

The role of the mucus-buffer layer includes partial neutralization of hydrogen ion diffusing towards the esophageal mucosa, retardation of the rate of diffusion of hydrogen ion, blocking diffusion of pepsin by serving as a substrate for its proteolytic activity, and retardation of diffusion of bile acids [1, 3, 4]. In patients with Barrett's esophagus the secretory capacity of columnar epithelium, in terms of mucin and buffers, helps the secretion from esophageal submucosal mucous glands in its mucosal protective combat against the potential injury by refluxate. Therefore, the thickness of the mucus- buffers layer is greater reaching 0.215 ± 0.035 µm [1]. Although this layer is adequate for mucosal protection and even elimination of heartburn symptoms in a subset of Barrett's esophagus patients, it fails, however, in other Barrett's esophagus subjects who subsequently develop LGD, HGD and ultimately adenocarcinoma [5]. Considering the fact that two virtually constant histologic features of dysplasia are mucin depletion and prominent cytoplasmic basophilia, one may assume that the thickness of the mucus layer in patients with Barrett's esophagus accompanied by LGD and especially HGD could be further significantly compromised. The thickness of the mucus-buffers layer and its ability to maintain the adequate pH gradient in patients with Barrett's esophagus at various stages of LGD, HGD, and adenocarcinoma requires further clinical exploration.

The continuous mucosal challenge with components of GER and DGER results in chronic inflammation within the columnar epithelium and increased generation of prostaglandin E2 (PGE2) as well as other mediators of chronic injury/repair phenomenon such as epidermal growth factor (EGF) and transforming growth factor a (TGFa) [6-12].

The topic of the potential role of prostanoids in health and disease of the esophageal squamous mucosa is complex, since prostaglandins have been claimed as protective by some authors and reputed as detrimental to the mucosal integrity by others [13-18].

The protective quality of PGE2 within the gastrointestinal columnar epithelium, however, is well established [19-21]. Since luminal PGE2 has an ability to enhance the physical properties of the mucus layer, especially to retard hydrogen ion diffusion, it could be of value in the pre-epithelial defense against GER [20]. Of note, as we have recently demonstrated the rate of secretion of PGE2 within the Barrett's mucosa is significantly (approximately 7 to 10-fold) higher than within the squamous epithelium [22]. Although one may anticipate that PGE2 could benefit the columnar mucosa facing the injurious factors of GER and DGER, prostaglandins in general and their analogue endoperoxides may also enhance cancer development through the LGD and HGD sequence acting, when exceeding their physiological range of concentrations, as co-carcinogens or tumor promoters [23, 24].

Prostaglandins are very sensitive markers of inflammation and/or injury to the alimentary tract mucosa and could be the most sensitive indicator of the injurious exposure of the columnar epithelium within the Barrett's mucosa to the refluxate components [25-27]. Therefore, monitoring the content of PGE2 within the columnar epithelium before and during treatment with proton pump inhibitor (PPI) could help to establish the most effective PPI dose. In addition, if during continuous therapy with PPI their levels exhibit increase this could potentially herald an increased risk of mucosal malignancy. To confirm their hypothetical role a prospective, long-term clinical study is urgently needed.

Both EGF and TGFa are elevated during the chronic injury/repair phenomenon since they are considered as a luminal mucosal surveillance and mucosal integrity peptides, respectively [9, 28, 29]. This may at least partly explain why both are also elevated within the Barrett's mucosa and, subsequently adenocarcinoma [10-12]. In addition, both EGF and TGFa are released into the lumen especially under the impact of the esophageal mucosal exposure to HCl and HCl/pepsin [30, 31]. One may anticipate, therefore, that measurements of EGF and TGFa within the Barrett's mucosa before and during long-term pharmacotherapy may help, in addition to the measurement of the level of PGE2, to tailor the most effective dose of inhibitors of gastric acid secretion, to established morphological and functional stability within the columnar epithelium, and potentially diminish the risk of progression to LGD, HGD and adenocarcinoma. This, however, still has to be regarded as a potential clinical research goal for the long-term surveillance study protocol.

References

1. Sarosiek J, McCallum RW. What is the secretory potential of submucosal mucous glands within the human gullet in health and disease? Digestion 1995;56):15-23.

2. Quigley EMM, Turnberg LA. pH of the microclimate lining human gastric and duodenal mucosa in vivo:Studies in control subjects and in duodenal ulcer patients. Gastroenterology 1987;92:1976-1984.

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. Namiot Z, Sarosiek J, Rourk RM, McCallum RW. Human esophageal secretion: mucosal response to luminal acid and pepsin. Gastroenterology 1994;106:973-981.

5. Clark GW, Smyrk TC, Mirvish SS, Anselmino M, Yamashita Y, Hinder RA, DeMeester TR, Birt DF. Effect of gastroduodenal juice and dietary fat on the development of Barrett's esophagus and esophageal neoplasia: an experimental rat model. Ann Surg Oncol 1994;1:252-261.

6. Wilson KT, Fu S, Ramanujam KS, Meltzer SJ. Increased expression of inducible nitric oxide synthase and cyclooxygenase-2 in Barrett's esophagus and associated adenocarcinoma. Cancer Res 1998;58:2929-2934.

7. Zimmermann KC, Sarbia M, Weber AA, Borchard F, Gabbert HE, Schror K. Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer Res 1999;59:198-204.

8. Shirvani VN, Ouatu-Lascar R, Kaur B, Omary MB, Triadafilopoulos G. Cyclooxygenase 2 expression in Barrett's esophagus and adenocarcinoma: ex vivo induction by bile salts and acid exposure. Gastroenterology 2000;118:487-496.

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

10. Yacoub L, Goldman H, Odze RD. Transforming growth factor alpha, epidermal growth factor receptor, and MiB-1 expression in Barrett's-associated neoplasia: correlation with prognosis. Mod Pathol 1997;10:105-112.

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