What is the role of epidermal growth factor in saliva in protecting the esophageal mucosa?
PJ. Kahrilas (Chicago)
Epidermal growth factor (EGF), also known as epithelial growth factor, urogastrone-EGF, and (3-urogastrone, is a single chain polypeptide secreted by the submandibular salivary glands, duodenal Brunner's glands, small intestinal Paneth cells, and other exocrine glands including the pancreas . EGF is found in several body fluids including saliva. Although circulating levels of the peptide are low, high concentrations are found within platelet granules. Transforming growth factor alpha (TGF-α) is a 50 amino acid peptide with 40% homology to EGF that acts on the same receptor. Both EGF and TGF-α are produced extracellularly on the cell membrane as precursor molecules which are then activated by proteolysis . Both peptides are found in many gastrointestinal tissues including the esophagus and stomach. Despite their shared receptor, EGF and TGF-α probably evoke distinct biological effects, by evoking distinct conformational changes in the receptor and activating different secondary messengers .
Epidermal growth factor receptor (EGF-R) is an integral plasma membrane glycoprotein. Activation of EGF-R by either EGF or TGF-α is mitogenic in cell culture studies of squamous cells, fibroblasts, and various mucosal tissues . The mitogenic action may be mediated by regulation of the transition rate between G2 phase and mitosis of the cell cycle . Of the two peptides, TGF-α is 10 times as potent mitogenically as well as possessing additional proliferative properties including increased cell ruffling, angiogenesis and megacolony formation . EGF and TGF-α have been invoked as potential causal factors in the development of Barrett's epithelium, dysplasia and carcinogenesis of the esophagus, because of the proliferative effects, although no more than an association has yet been demonstrated . The remainder of this discussion, however, will focus only on the role of salivary EGF on the maintenance of esophageal mucosal integrity.
In vivo actions of EGF in the gastrointestinal tract include promoting wound healing, inducing cellular proliferation, promoting differentiation, and potentially oncogenesis . EGF is immunohistochemically detectable in all layers of the esophageal epithelium, with greatest density in the basal layer compared with the more superficial layers . EGF localizes in the capillary endothelium of the normal esophageal papillae and basal mucosa. However, significantly more EGF positive papillae are found in the normal mucosa as opposed to the inflamed mucosa . This leads to a question of cause and effect, with some investigators hypothesizing that a deficiency of secreted EGF is a cause of erosive esophagitis, whereas other investigators suggest that diminished detection in the mucosa may be an effect of inflammation. The latter hypothesis seems more likely since there are no demonstrable differences in salivary EGF levels among individuals with a normal mucosa, gastritis, or erosive esophagitis . Controversy persists, however, as to whether or
In part, the above controversy revolves around the origin of EGF found in esophageal tissue. EGF is found in the endothelium of normal capillaries immediately adjacent to the basal cells of the esophageal epithelium and deep esophageal glands. Thus, it is not immediately apparent how luminal EGF contained in saliva could localize to these deep layers of the epithelium. An alternative hypothesis is that EGF is transported to the basal cell layers via platelet EGF; an attractive hypothesis considering where EGF localizes. It has been experimentally demonstrated that EGF administered intravenously exhibits much greater trophic effects than does EGF administered intraluminally . Perhaps, EGF is stored in the endothelial cells of the normal mucosa and is rapidly released and utilized when inflammation occurs. Thus, the observation that mucosal EGF is depleted in peptic esophagitis is better explained by the observation that EGF has a relatively short half life (< 24 h) than by the hypothesis that EGF depletion led to the development of, or susceptibility to esophagitis . However, not all experimental evidence agrees with this hypothesis. There is some experimental evidence supporting the role of salivary EGF in maintenance of the esophageal mucosa. Specifically rats, subject to sialoadenectomy, demonstrate increased mucosal permeability to hydrogen ion and this increased permeability is partially reversed by the intraluminal administration of EGF . Bear in mind, though, that there is more in saliva than just EGF and this experiment might simply be verifying the importance of saliva in mucosal defense.
Another interesting hypothesis regarding the role of salivary EGF is that it acts to stimulate ulcer healing throughout the gut. Areas denuded of normal epithelium would be accessible to luminal EGF and presumably EGF could bind at these sites and stimulate cellular proliferation adjacent to the ulceration. In this capacity, it has also been reported that salivary EGF is bound to sucralfate and bismuth, agents that bind to the base of ulcers and possess "cytoprotective" properties [13,14]. This would then be the explanation for those cytoprotective properties.
5. Kinzel V, Kaszkin M, Blume A, Richards J Epidermal growth factor inhibits transiently the progression from G2 phase to mitosis; a receptor mediated phenomenon in various cells. Cancer Res 1990;50:7932-7936.