Hypergastrinemia and gastric hypoacidity in rodents : causes and consequences
Abstract
Gastrin and gastric aciditity are phylogenetic old parts of the digestive system developed for more than 400 million years ago, released into the bloodstream from the antral gastrin (G) cell, is the main hormone regulating the gastric acid secreation and the growth of the oxyntic mucosa. The G cells are "open type " edocrine cells that are able to detect, sample and respond to luminal content. Somatostatin released from adjecent "open-type" D cells provides a paracrine tonic inhibition of gastrin release from G cells. The main luminal stimuli for gastrin release are reduced gastric acidity, amino acids and calcium.
Previously, ciprofibrate, a peroxisome proliferator used as a hypolipidemic drug, has been shown to induce hypergastrinemia and ECL cell carcinoids in the oxyntic mucosa in rats. It was suggested that the mechanism was ciprofibrate-induced inhibition of gastric acid sectretion. However, the level of hypergastrinemia was disproportionately high compared to the insignificant decrease in gastric acidity. Therefore we re-examined the effect on gastric acidity and we demonstrated that ciprofibrate induces hypergastrinemia without reducing gastric acidity (I). This strongly indicates a direct effect pn the G cell. Subsequently, the hypergastrinemia induced by ciprofibrate was shown to be secondary to an increased storage and synthesis of antral gastrin and it was accompanied by G cell hyperplasia (II). The effects on the G cell were independent of gender and strain of rats (II). During ciprofibrate dosing a concomitant increase in gastrin and somatostatin mRNA abundance in the antral mucosa was found (II). To our knowledge, this has not been reported previously since there seem to exist a reciprocal relationship between the activity of the antral G cell and the somatostatin producing D cells. Since oxyntic D cells are of the closed type and the abundance of somatostatin mRNA in the oxyntic mucosa was decreased during ciprofibrate dosing (paper(II), it is reasonable to suggest that luminal ciprofibrate acts locally on the endocrine cells of the open type.
The morphological hallmark of G cells is the heterogeneous composition of granule types spanning from small electron dense to large electron lucent. It has been concluded that the small electron ense granules are newly formed and immature, containing gastrin precursors. These granules are converted into the larger electron lucent ones during enzymatic modification of their content. Ciprofibrate induces extensive changes in granule morphology and composition in G cells (III). The most conspicuous findings are shift of granule-type composition towards immature electron-dense granules and the decrease in total granule number per cell. These changes are quite similar to those induced by pantoprazole, indicating signs of G cell activation in general. However, distinctions concerning granule size and compositon and both hypertrophy and hyperplasia of G cell were found.
Peroxisomes have not been described in G cells previously. As proliferation of peroxisomes is one of the well-known responses to ciprofibrate dosing, it was of interest to identify these organelles in the gastrin producing cell. Demonstration of peroxisomes in G cells was achieved by using the tyramide signal amplification technique in the immunostaining of the peroxisome-specific protein PMP-70 (III). Peroxisomes were not found in G cells by the use of routine electron microscopy and immune electron microscopy. Consequently, it is suggested that these organells are rather rare in G cells (III).
Gastric acidity is found in a large number of animals ranging from fish to mammals and the preservation of this highly energy consuming (H+concentration in the gastric juice is 3 million times greater than in blood and tissue) and sometimes pathogenic (acid related diseases) system reflects its importance. Gastric acid denatures proteins and activates pepsinogens. However, the main purpose of the gastric acid is to inactivate swallowed micro-organisms. At pH below 4 the gastric juice has a rapid bactericidal effect, in which exogenous bacteria introduced into the stomach are usually destroyed within 15 min. The bactericidal effect is reduced at a PH above 4.0. It is of interest that in healthy subjects gastric acidity is maintained with a pH<4.0, and is similar to the pH level at which the inhibition of gastrin relaease from the antral G cells stops. It has been repeatedly demonstrated that reduction of gastric acid secretion predisposes to infection with a variety of micro-organisms. Prion diseases are degenerative disorders of the central nerve system leading to motor dysfunction, dementia and death. The prions, supposted to be infective proteins lacking nucleic acids, have recently attracted much public attention due to proposed link between bovine spongiform encephalopathy (BSE) in cattle and the occurrence of a new varient of Creutzfeldt-Jakob disease (vCJD) in humans. Hitherto, this disease has affected more than a hundred individuals in the UK. To predict the scale of the epidemic seems virtually impossible because both the number of induviduals with subclinical infection and the incubation period of these agents in humans are unknown. There has been a lack of studies concerning the role of gastric acidity in the protection aganinst prion infections. Prions are very resistant to inactivation both by acid and proteases. However, we postulated that the unique combination of profound acidity and the active proteolytic enzyme, pepsin, found in gastric juice, could damage prions and reduce their infectivity. The results in study IV suggests that even a moderate increase is gastric pH makes iced more susceptible to infection with a scrapie agent (prion protien fron sheep). Consequently, normal levels of gastric acidity seems to protect mice to some extent from infection with low loses of prions (IV). This finding is potentially relevant to the pathogenesis of varient Creuzfeldt Jakobs disease. Moreover, ingestion of infective prions during and/or shortlt after acute gastroenteritis, which is often accompanied by a transient gastric hypoacidity, may therefore represent a high-risk incident. It is also reasonable to speculate that the use of antisecretagogous drugs might have enhanced the susceptibility of individuals to variant Creutzfelt-Jakob disease.
Gastrin is the most important growth factor in the oxyntic mucosa and the main target is the ECL cells. "The gastrin hypothesis" has been known for several years explaining the relationship between hypergastrinemia, induced by inhibition of gastric acid secretion, and formation of gastric acid secretion, and formation of gastric carcinoids. The pathogenesis is hyperplasia of the ECL cells, proceeding gradually from diffuse hyperplasia via a liniar to one of micronodular type. If hypergastrinemia persists this may ultimately leads to dysplasia and intramucosal microcarcinoid, and subsequently into a genuine foregut carcinoid of ECL cell type. The association between hypergastrinemia and ECL cell carcionoids is accepted for both animals and humans. By contrast, the role of gastrin and the ECL cell in the formation of gastric adenocarcinomas has been a controversy for more than a decade.
Recently, the spontaneous gastric tumors in female cotten rats were classified as invasive ECLomas, and it was suggested that the high incidence of such tumors was due to long-standing hypergastrinemia secondary to an as yet unexplained gastric hypoacidity. Fifty percent of these female cotten rats develop hypoacidiity apontaneously, which leads to hypergastrinemia (V). The hypergastrinemia induces firsst diffuse and then focal ECL cell hyperplasia and dysplasia. Ultimately, after four months, ECL cell carcinomas are formed as the tumors are able to penetrate the stomach wall and to metasasize by intravital seeding. These finding supports the view that neoplasms derived from ECL cells may be highly malignant. Inbred female cotton rats represent a unique hypergastrinemia model allowing detailed studies of the spontaneous multistep development of malignat ECL cell derived tumors.
During the last decade specific and efficient gastrin receptor antagonists have become available. These antagonists inhibit gastric acid secretion in rodents and dogs and may be potentially useful in the treatment of acid-related diseases. Well-known potential side effects of the long-term hypergastrinemia that follows upon acid inhibition, such as a trophic effect on the oxyntic mucosa (notably ECL cell hyperplasia, dysplasia and neoplasia) and rebound acid hypersecretion, are unlikely to occur following treatment with gastrin receptor antagonist YF476 lowered the incidence of spontaneous ECL cell carcinomas in female cotten rats (v). This finding illustrates the fact that gastrin promotes the develoment of ECL cell derived mal
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Doktoravhandlinger ved NTNU, 1503-8181Dissertations at the Faculty of Medicine; 222