Is ablation of the esophageal columnar tissue more likely to induce restoration of squamous epithelium than just acid suppression?
M.M. Berenson (Salt Lake City)
Glandular epithelium that lines the distal esophagus is thought to develop as a consequence of metaplastic re-epithelialization of injured or denuded stratified squamous esophageal mucosa. The glandular epithelium may evolve gradually or rapidly . Bremner et al.  found that regeneration of denuded esophageal mucosa in dogs occurred with squamous epithelium unless reflux of gastroduodenal contents was present in which case glandular tissue developed. They suggested the tissue extended from the gastric mucosa. Presumably, noxious components of the refluxate prevented normal squamous tissue regeneration. Gillen et al.  also found that columnar tissue regenerated in place of denuded stratified squamous esophageal tissue of dogs that refluxed gastric contents, but extension of gastric mucosa into the esophagus was precluded by separating the denuded area of the esophagus from the stomach by a strip of squamous tissue. They suggested the glandular epithelium originated from cells that lined the ducts of the esophageal cardiac glands. Using this canine model, it was subsequently shown that glandular tissue could re-epithelialize denuded areas of squamous epithelium in an anacid environment. Only the presence of islands of squamous tissue mixed into the glandular epithelium differentiated dogs with an anacid environment from dogs with free acid reflux . These observations suggest that esophageal columnar epithelium may develop in the absence of acid reflux. The source of the islands of tissue could be the proximal superficial squamous cells that line the ducts of the esophageal cardiac glands , persistent microscopic foci of normally-differentiated squamous epithelium within the glandular tissue, or primordial stem cells.
Metaplastic tissue has the potential to revert to normal . Both medical [6, 7] and surgical [8-10] therapy to reduce gastric acid secretion, and gastroesophageal reflux have been reported to induce regression of Barrett's epithelium. However, the reports have been infrequent [11-13] and controversial . More commonly, macroscopic and microscopic islands of squamous epithelium have been detected in Barrett's epithelium after antireflux surgery  and long-term acid suppression [11, 12]. Squamous tissue has been observed to grow over glandular epithelium .
We hypothesized that squamous epithelium could be restored to areas of columnar mucosa if the established columnar tissue was ablated and the presence of noxious agents was reduced during the time the esophageal epithelium healed . Argon laser was used to ablate glandular tissue in locations that varied from "islands," totally surrounded by squamous tissue to "patches," totally surrounded by glandular tissue. Gastric acid secretion was suppressed with 40 mg omeprazole daily during the period of re-epithelialization. Normal appearing squamous tissue was partially or totally restored in 38 of 40 treatment locations. No change occurred in Barrett's epithelium that was not treated. Destruction of esophageal glandular tissue using thermal devices [17-21] or photodynamic treatments [22, 23] have subsequently been reported to facilitate squamous tissue re-epithelialization. But, this experience is not without exception . In all cases, antireflux surgery and/or medical treatment to reduce acid secretion and gastroesophageal reflux have been applied during the regenerative period. No study in humans has systematically evaluated the role of acid or other components of the gastroesophageal refluxate on the regenerative process. There are three reasons for which it is generally concluded that anacidity favors normal esophageal tissue regeneration:
1) gastroesophageal acid reflux is the principal pathogenetic factor in Barrett's esophagus,
2) an acid environment promoted glandular tissue formation in animal studies,
3) successful restoration of squamous epithelium has been reported in an anacid but not an acid environment .
Although the precise mechanisms responsible for restoration of squamous tissue after ablation of the metaplastic glandular tissue are not known, an explanation can be proposed based upon studies of wound healing of the skin, an organ with keratinized stratified squamous epithelium [26-29]. Wound healing is a complex process that has been separated into three overlapping phases: inflammation, tissue formation, and tissue remodeling. These phases are distinguishable by specific soluble and insoluble mediators and cellular elements integral to inflammation, cell migration, angiogenesis, matrix synthesis, collagen deposition and re-epithelialization. Regulation of the interplay of growth factors, cytokines, matrix molecules, and epithelial-mesenchymal cell interactions that orchestrate the healing phenomenon, however, remains unclear.
Injury that disrupts the continuity of the stratified squamous epithelium induces signals to repair the rent and reestablish epithelial integrity. In the esophagus, normal squamous tissue re-epithelialization may be perturbed by agents that directly affect pluripotent stem cells or progenitor cells. Squamous tissue re-epithelialization may also be perturbed indirectly by altering growth factors, cytokines, and other elements that regulate the reparative process. As mentioned, animal experiments indicate that the presence of acid in the environment of injured esophageal mucosa impedes normal squamous tissue re-epithelialization. Acid may directly affect epithelial cell proliferation and differentiation, but it is more likely that the process is disturbed by the persistence of inflammation induced by the acid. Inflammation is known to impair healing and induce histopathologic features of dysplasia. Inflammation is probably responsible for the morphologic characteristics described at the squamocolumnar junction in Barrett's epithelium . The diverse array of morphological and functional phenotypes present in the glandular tissue favor derivation from a primordial stem cell. Presumably, acid and inflammation promote the development of metaplastic esophageal columnar tissue which is able to close the breech in the epithelium and restore tissue continuity.
Stem cells in the proliferative compartment of the glandular tissue are regulated and constrained by needs of the epithelium-renewal of surface cells and repair of tissue injuries including acid-induced ulcerations that may disrupt the mucosa. There are no data to support the notion that an anacid environment induces the stem cells in the glandular mucosa to revert to a squamous pathway of differentiation. Restoration of squamous epithelium in Barrett's esophagus can be facilitated by eradication of the abnormal glandular mucosa. It appears that the wound produced by ablation of the glandular tissue can be re-epithelialized in a normal fashion if reflux and its attendant injury and inflammation are reduced or eliminated. The restored squamous epithelium could be derived from any of the potential progenitor sources within the esophagus. Clearly, there is a need to clarify the fundamental processes regulating esophageal mucosal repair.
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