Structure and function of gastric corpus mucosa in suckling rats after treatment with 16,16-dimethyl prostaglandin E2

Suckling rats were treated every 8 h by intragastric instillation of 16,16-dimethyl prostaglandin E₂ (PG) from postnatal day 7 to 11. As compared to saline control treatment, PG increased the thickness of antral and corpus mucosa, the volume density of parietal cells, the mean individual parietal cell volume and pentagastrin-stimulated acid secretion at the end of the treatment. Plasma gastrin and corticosterone levels were depressed by PG while plasma thyroxine levels were unchanged. These structural and functional changes suggest PG-induced accelerated maturation of gastric mucosa.     

Hypergastrinaemia produces trophic effects in stomach but not in pancreas and intestines

Hypo- or anacidity, caused by antisecretagogues, stimulates gastrin release and leads to hypergastrinaemia. If drug treatment is maintained over a period of time, the hypergastrinaemia can be expected to give rise to trophic effects. We examined the trophic consequences of the very marked hypergastrinaemia produced by long-term treatment (16-20 weeks) of rats with large doses of the substituted benzimidazole, omeprazole, a potent and long-acting blocker of acid secretion. The weight of the stomach and the oxyntic mucosal thickness were increased, whereas the weight of the pancreas and the intestines and the thickness of the mucosa of the antrum and small and large intestine were unaffected. The number of exocrine cells (parietal, zymogen and mucous cells) were uniformly increased by 25-30%. The density of parietal and zymogen cells, expressed as number of cell nuclei per mm2 epithelium, was unchanged. The volume density of parietal cells, expressed as % of epithelial volume, was also unchanged, implying that the volume of the individual parietal cell had not increased. The density of endocrine ECL cells in the stomach increased 5-fold. Thus, the findings demonstrate a growth-promoting effect of the hypergastrinaemia on the oxyntic mucosa, the ECL cells in particular, and the lack of such an effect on the antrum, pancreas and intestines.     

Prostaglandins and prostaglandin metabolites in human gastric juice

Human gastric juice contains higher concentrations of PG metabolites than of unmetabolized PG indicating that local metabolism might play a role in limiting the biological activity of PG in gastric mucosa and has to be considered when investigating endogenous gastric PG. A major fraction of the 15-keto-13,14-dihydro-PGE2 (KH2PGE2) formed in gastric mucosa and released into the gastric lumen seems to be rapidly dehydrated to a compound co-chromatographing with KH2PGA2, while the amounts of the bicyclic degradation product 11-deoxy-13,14-dihydro-15-keto-11,16-cyclo-PGE2 (11-deoxy-KH2-cyclo-PGE2), as measured by radioimmunoassay, in freshly extracted gastric juice are negligible. Stimulation of secretion with pentagastrin does not influence significantly the concentrations of PG and PG metabolites in human gastric juice, but total output tends to increase parallel to the increase in secretion volume. Levels of immunoreactive 6-keto-PGF1 alpha in human gastric juice are much lower than those of PGE2. Since human gastric mucosa synthesizes conciderable amounts of PGI2 and 6-keto-PGF1 alpha in vitro, the low levels of 6-keto-PGF1 alpha in gastric juice might indicate that PGI2 formed by gastric mucosa in vivo is, like PGE2 and PGF2 alpha, rapidly metabolized and/or removed preferentially via the blood stream.     

Morphometric studies of parietal cells in cats before and after lesser-curvature seromyotomy

A modified, highly selective vagotomy-seromyotomy of the lesser curvature of the stomach was performed on five groups of cats. The horseradish peroxidase (HRP) tract-tracing method was used to detect the regeneration or reinnervation of vagal nerve branches. Morphological changes to the parietal cells and to the gastric mucosa were also examined by light and electron microscopy. Following surgery, the cats were sacrificed at the fourth, eighth, twelfth, sixteenth and the twentieth week. At the sixteenth week, partial regeneration of vagal nerve branches was found. Between the fourth and the twelfth week there was a significant increase in the number of parietal cells per 0.1 mm-wide of mucosa column and in the volume fraction of the mucosa made up of parietal cells. Of the four types of parietal cells, "stimulated", "partially stimulated", "returning" and "resting", the resting type was predominant after seromyotomy, especially between the fourth and the twelfth week. Based on the above observation, we concluded that the modified lesser-curvature seromyotomy depresses the function and responsiveness of the parietal cells despite an increase in their number and in their volume fraction.     

Role of Na-K-2Cl cotransporter-1 in gastric secretion of nonacidic fluid and pepsinogen

Na-K-2Cl cotransporter-1 (NKCC) has been detected at exceptionally high levels in the gastric mucosa of several species, prompting speculation that it plays important roles in gastric secretion. To investigate this possibility, we 1) immunolocalized NKCC protein in the mouse gastric mucosa, 2) compared the volume and composition of gastric fluid from NKCC-deficient mice and their normal littermates, and 3) measured acid secretion and electrogenic ion transport by chambered mouse gastric mucosa. NKCC was localized to the basolateral margin of parietal cells, mucous neck cells, and antral base cells. In NKCC-deficient mice, gastric secretions of Na+, K+, Cl-, fluid, and pepsinogen were markedly impaired, whereas secretion of acid was normal. After stimulation with forskolin or 8-bromo-cAMP, chambered corpus mucosa vigorously secreted acid, and this was accompanied by an increase in transmucosal electrical current. Inhibition of NKCC with bumetanide reduced current to resting levels but had no effect on acid output. Although prominent pathways for basolateral Cl- uptake (NKCC) and apical Cl- exit [cystic fibrosis transmembrane conductance regulator (CFTR)] were found in antral base cells, no impairment in gastric secretion was detected in CFTR-deficient mice. Our results establish that NKCC contributes importantly to secretions of Na+, K+, Cl-, fluid, and pepsinogen by the gastric mucosa through a process that is electrogenic in character and independent of acid secretion. The probable source of the NKCC-dependent nonacidic electrogenic fluid secretion is the parietal cell. The observed dependence of pepsinogen secretion on NKCC supports the concept that a nonacidic secretory stream elaborated from parietal cells facilitates flushing of the proenzyme from the gastric gland lumen.     

Glucose, insulin, pancreatic glucagon and glucagon-like immunoreactive materials in the plasma of normal and diabetic children. Effect of the initial insulin treatment.

Pancreatic glucagon (PG) and other glucagon-like immunoreactive materials (GLI) were measured in the plasma of normal and of newly diagnosed untreated diabetic children, using an antiglucagon serum (AGS) highly specific for pancreatic glucagon (AGS 18) and an AGS which crossreacts with extracts of intestinal mucosa (AGS 10). Gut GLI was considered to be the difference between "total" GLI (AGS 10) and PG (AGS 18). Glucose and immunoreactive insulin (IRI) were also measured. PG, total GLI and gut GLI were significantly elevated in children with severe insulin insufficiency and were reduced to normal by insulin treatment, even though a significant fasting hyperglycemia was still present. In three diabetic children who had high initial plasma IRI levels the three glucagon fractions were normal. We conclude that insulin insufficiency is characterized not only by high plasma levels of PG as previously reported, but also of gut GLI. These abnormalities can be corrected by the administration of insulin.     

Localization of pepsinogen and cellular differentiation in the human gastric mucosa using lowicryl K4M

The localization of pepsinogens (PG A and PG C) was studied intracellularly in human gastric biopsies embedded in Lowicryl K4M, using affinity purified antibodies and protein A-gold. The homogeneous secretory granules of the chief cells contained both PG A and PG C, as was proved in serial sections. Identical reaction was seen in the core of the biphasic mocous neck cell granules, whereas the mantle did not label. Even the rough endoplasmic reticulum (RER) and Golgi complex of the chief- and mucous neck cells contained label. Transitional cells identified by the presence of granules of both chief- and mucous neck cells were seen. This type of mucous neck cell is thought to transform into a chief cell. However an increase of RER that could explain an increase of the pepsinogen production was not observed. A mixture of these granules were also found in morphologically characterized young parietal cells, suggesting a common precursor for these three cell-types. These observations makes the transformation from mucous neck- into chief cells questionable. In conclusion Lowicryl K4M appeared to be a significant improvement compared to the Epon 812. Its shows a better preservation of both cytoplasmic antigens and cellular fine structure. This improvement adds information on the transformation hypothesis. Lowicryl K4M enables us, firstly to distinguish PG A and C synthesizing RER in different types of cell and secondly to recognize immature cells with the characteristics of chief-, mucous neck-, and parietal cells in the fundic gland. Very likely these three cell-types all arise from a common precursor. It is questionable that in normal human gastric mucosa the mucous neck cells transform into chief cells.     

Prostaglandins and prostaglandin metabolites in human gastric juice

Human gastric juice contains higher concentrations of PG metabolites than of unmetabolized PG indicating that local metabolism might play a role in limiting the biological activity of PG in gastric mucosa and has to be considered when investigating endogenous gastric PG. A major fraction of the 15-keto-13,14-dihydro-PGE₂ (KH₂PGE₂) formed in gastric mucosa and released into the gastric lumen seems to be rapidly dehydrated to a compound co-chromatographing with KH₂PGA₂, while the amounts of the bicyclic degradation product 11-deoxy-13,14-dihydro-15-keto-11,16-cyclo-PGE₂ (11-deoxy-KH₂-cyclo-PGE₂), as measured by radioimmunoassay, in freshly extracted gastric juice are negligible. Stimulation of secretion with pentagastrin does not influence significantly the concentrations of PG and PG metabolites in human gastric juice, but total output tends to increase parallel to the increase in secretion volume. Levels of immunoreactive 6-keto-PGF_1α in human gastric juice are much lower than those of PGE₂. Since human gastric mucosa synthesizes considerable amounts of PGI₂ and 6-keto-PGF_1α in vitro, the low levels of 6-keto-PGF_1α in gastric juice might indicate that PGI₂ formed by gastric mucosa in vivo is, like PGE₂ and PGF_2α, rapidly metabolized and/or removed preferentially via the blood stream.     

Stimulation of prostaglandin synthesis in rabbit gastric antral mucosal slices by desferrioxamine in vitro.

Desferrioxamine is an iron-chelating agent used in the treatment of iron overload. It is a powerful inhibitor of iron-dependent radical reactions. The effect of desferrioxamine of prostaglandin (PG) synthesis and metabolism in rabbit gastric antral mucosal slices has been examined. Desferrioxamine significantly enhanced the production of PGE2 and PGF2 alpha. The formation of 13,14-dihydro-15-keto PGE2 and 13,14-dihydro-15-keto PGF2 alpha was also increased slightly by desferrioxamine. The addition of Fe3+ or Al3+ blocked the stimulatory action of desferrioxamine on PGE2 and PGF2 alpha production. Desferrioxamine appears to be stimulating the activity of PG cyclooxygenase through the removal of endogenous antral mucosal iron. These results suggest that desferrioxamine has the potential to increase the PG levels in gastric mucosa by primarily stimulating PG biosynthesis. The possibility that desferrioxamine may be of therapeutic value in the treatment of ischemic injury in the stomach is discussed.     

Prostaglandins in chronic cholecystitis

Prostaglandin-like material was extracted from the mucosa and muscle wall of chronically inflamed human gallbladders. Bioassay showed that “synthesised” levels were 3–5 times corresponding “basal” levels, indicating that both mucosa and muscle wall can synthesise PG-like substances, and that indomethacin (10μg/ml) inhibited this synthesis. Mucosal PG levels were higher in gallbladders with multiple gallstones than with a solitary stone, and overall the mean PG level in mucosa was 12–13 times higher than in the muscle wall. Chromatography of mucosal extracts showed substances indistinguishable from primary PGE and F compounds together with a PGD₂-like component. An attempt has been made to relate these findings to the degree of chronic inflammatory cell infiltration and to radiological visualisation at pre-operative cholecystography.     

Genetic and evolutionary implications in peptic ulcer disease

The evidence for a genetic component in peptic ulcer disease has been based on twin, family, and blood group studies. A polygenic model for the inheritance of peptic ulcers has been displaced by a genetic heterogeneity model based on several lines of evidence, some of the most powerful being recent work using subclinical markers. One marker in particular, an elevated level of serum pepsinogen I (PG I), a pepsin precursor produced by the gastric mucosa, secreted into the stomach lumen and also appearing in the bloodstream, has been found to be associated with a subgroup of duodenal ulcer patients. Segregation analysis of elevated serum PG I in duodenal ulcer sibships demonstrates familial aggregation consistent with autosomal dominant inheritance. Elevated PG I is also accompanied by gastric hyperacidity and presumably indicates those individuals with an increased mass of chief and parietal cells, and thus an increased capacity for peptic activity, an important element in the pathogenesis of ulcer disease. An evolutionary hypothesis based on selection for peptic activity and acidity is offered to explain several of the epidemiologic and genetic elements of this group of chronic diseases.     

Effect of long-term prostacyclin treatment on the gastric mucosa of rat

According to Bálint and Varró, oral administration of prostacyclin (PGI2) resulted in a significant increase of the DNA-content of the gastric mucosa within a short period of time. In the present study, there was no change in the protein content of the gastric mucosa after oral administration of 100 micrograms/kg/day of PGI2 for 80 days, while the DNA-content increased significantly. The RNA/DNA ratio decreased. Histologically a significant increase in the thickness of the gastric mucosa, as well as in the number of parietal and epithelial cells were found. The cell hyperplasia in the corpus mucosa was accompanied by a decreased number of G-cells of the antral mucosa. The increase of parietal cell number and the decrease of G-cell number after long term PGI2 administration might be explained by the divergent effect of treatment on the kinetics of the different cell types in the gastric mucosa.     

Topographic features of the ultrastructure of parietal cells of the gastric mucosa (morphometric study)]

A new methodical approach to the study of the ultrastructure of the parietal cells of the gastric mucosa is suggested. Electron microscopic study of peculiarities of the submicroscopic cell organization at the three main levels (the generative zone, the zone of the most active cells, and the gland floor) is necessarily followed by the morphometric analysis of the results obtained. Marked differences in the ultrastructural morphometric indices of the parietal cells located at various levels of the glands were demonstrated with the aid of the mentioned method. Despite certain difficulties, such approach can be also applied to the study of other cell elements of the gastric mucosa and also of many other tissues with continuous quick cell renewal.     

Implication of gastrin in cyclooxygenase-2 expression in Helicobacter pylori infected gastric ulceration

Gastroduodenal ulcerations have worldwide distribution and the infection with Helicobacter pylori (HP) has been implicated in pathogenesis of this disease. The HP infection is usually accompanied by hypergastrinemia and enhanced generation of prostaglandins (PG), both implicated in the pathogenesis of peptic ulcerations but no study has been undertaken to assess the relationship between the HP infection and coexpression of gastrin and cyclooxygenases (COX), the rate limiting enzymes in the PG production. Since HP infection, usually accompanying peptic ulcerations, results in increased release of gastrin, a potent gastric mitogen that might be capable to induce COX-2 and to generate PG, we decided 1) to compare the seroprevalence of HP and its cytotoxic protein, CagA, in gastric ulcer patients with those in age- and gender-matched controls; 2) to determine the gene expression of gastrin and its receptors (CCK(B)-R) at the margin of gastric ulcer and in the mucosa of antrum and corpus before and after successful eradication of HP, 3) to assess the plasma levels and gastric luminal contents of gastrin before and after HP eradication and 4) to examine the mRNA and enzyme protein expression of COX-1 and COX-2 as well as the PGE2 generation in ulcer margin tissue and gastric antral and fundic mucosa before and after the HP eradication. The trial material included 20 patients with gastric ulcer and 40 age- and gender-matched controls. Anti-HP and anti-CagA IgG seroprevalence was estimated by specific antisera using ELISA tests. Gene expressions of gastrin, CCK(B)-R, COX-1 and COX-2 were examined using RT-PCR with beta-actin as a reference and employing Western blotting for COX-2 expression, while gastrin and PGE2 were measured by RIA. All gastric ulcers were located at smaller curvature within the antral mucosal area. The seroprevalence of HP, especially that expressing CagA, was significantly higher in gastric ulcers (85%) than in controls (62.5%). Both gastrin and CCK(B)-R mRNA were detected by RT-PCR in ulcer margin and gastrin mRNA was overexpressed in remaining antral mucosa, while CCK(B)-R mRNA was overexpressed in fundic mucosa of HP infected patients. Similarly, COX-2 mRNA and protein were found in margin of gastric ulcer and in the HP infected antral and fundic mucosa but not in the mucosa of HP eradicated patients in whom ulcers completely healed and gastrin was expressed only in antrum, CCK(B)-R only in corpus, while COX-1 was detected both in antrum and corpus. HP positive gastric ulcer patients showed about three times higher levels of plasma immunoreactive gastrin and about 50% higher luminal gastrin contents than the HP negative controls and this increased plasma and luminal gastrin was normalized following the HP eradication. A significant fall in gastrin and CCK(B)-R mRNA expression was noticed six weeks after HP eradication in gastric antral and fundic mucosa, while COX-2 mRNA completely disappeared after this treatment. We conclude that 1) HP infected gastric ulcer margin coexpresses gastrin, its receptors (CCK(B)-R), and COX-2; 2) HP infection may be implicated in gastric ulceration via increased release of gastrin that could be responsible for the overexpression of COX-2 that in turn could help ulcer healing through the stimulation of mucosal cell growth, restoration of the glandular structure and angiogenesis in the ulcer area and 3) gastrin produced in HP infected antral mucosa seems to be involved in the induction of COX-2 and PG production by this enzyme and this may contribute to the ulcer healing.     

应激状态下NO的胃粘膜保护作用及其与壁细胞泌酸的关系

目的:探讨应激状态下一氧化氮(NO)的胃粘膜保护作用及其与壁细胞泌酸的关系.方法:采用水浸-束缚应激(WRS)方法制备应激性溃疡(SU)动物模型,检测胃粘膜溃疡指数(UI)、胃粘膜NO含量和壁细胞H ,K -ATPase活性,观察L-硝基精氨酸甲酯(L-NAME)和L-精氨酸(L-Arg)对应激后大鼠壁细胞H ,K -ATPase活性及胃粘膜损伤的影响.结果:L-NAME(20 mg·kg-1)可使胃粘膜NO含量减少(P＜0.01),壁细胞H ,K -AT-Pase活性增加(P＜0.05),并加重应激所致的胃粘膜损伤;L-Arg(300 mg·kg-1)则使胃粘膜NO含量增加(P＜0.01),壁细胞H ,K -ATPase活性下降(P＜0.05),减轻应激所致胃粘膜损伤.结论:NO对应激状态下大鼠胃粘膜具有保护作用,其机制与抑制壁细胞H ,K -ATPase活性有关.     

Prostaglandin profile and synthetic capacity of the colon: comparison of tissue sources and subcellular fractions.

Although there has been intense interest in the physiology and pathophysiology of prostaglandins (PGs) synthesized in the colon, little is known about the PG profile and synthetic capacity of different tissue sources and subcellular fractions as enzyme sources. Subcellular fractions prepared from the mucosa and muscle layer of rat colon were incubated with or without exogenous arachidonic acid ([3H]20:4n-6) for 30 min. In experiments with exogenous [3H]20:4n-6, the prostaglandin synthetic capacity of the colonic muscle layer was significantly higher than that of the mucosa. Among the subcellular fractions, microsomes had the highest PG synthetic capacity in both mucosa and muscle. The major PG product was PGI2 and PGD2 in the mucosal microsomes and PGI2 and PGE2 in the muscularis microsomes. However, production of PGI2 in the mucosa and PGE2 in the muscle was significantly reduced in the fractions containing both cytosol and microsome, resulting in an alteration of the PG profile. Substrate availability (exogenous vs endogenous supply) appears to influence the PG profile of the colon. In the colonic mucosa with exogenous [3H]20:4n-6, the production of PGI2 was 5 times higher than that of PGE2, whereas the production of PGE2 was twice higher than that of PGI2 in experiments with endogenous 20:4n-6. These observations indicate: 1) different PG profile and synthetic capacity of tissue sources and subcellular fractions; 2) alteration of PG profile due to the variation of 20:4n-6 availability. Thus, the outcome of experiments on the physiological role of PG in the colon may be determined, in part, by the tissue source and subcellular fraction selected for analysis. The present study also suggests that the variation of substrate availability in physiological and pathophysiological processes may affect the PG profile of the colon.     

健胃消痞汤联合雷贝拉唑治疗慢性萎缩性胃炎的临床疗效及对血清G-17、ET-1、胃蛋白酶原、EGF及NO水平的影响

目的:探讨健胃消痞汤联合雷贝拉唑治疗慢性萎缩性胃炎(chronic atrophic gastritis,CAG)的临床疗效及对血清胃泌素-17(G-17)、内皮素-1(endothelin-1,ET-1)、胃蛋白酶原、表皮生长因子(EGF)及一氧化氮(NO)水平的影响。方法:选择2015年6月到2017年3月我院收治的100例CAG患者,随机分为对照组和治疗组,每组各50例。对照组患者给予雷贝拉唑治疗,治疗组患者在对照组治疗的基础上联合健胃消痞汤治疗,两组患者均治疗8周。评价并比较两组患者的临床疗效、治疗前后血清G-17、ET-1、胃蛋白酶原I(PG I)、胃蛋白酶原II(PG II)、EGF及NO水平的变化及治疗期间不良反应的发生情况。结果:治疗后,治疗组患者的总有效率为94.00%,明显高于对照组(78.00%)(P=0.021);两组患者血清G-17、PG I、PG II及NO水平均较治疗前明显升高,血清ET-1和EGF水平均明显下降,且治疗组以上指标的改善情况均显著优于对照组(P0.05)。两组患者治疗期间不良反应的发生率比较差异无统计学意义(P=0.461)。结论:健胃消痞汤联合雷贝拉唑治疗CAG的临床疗效显著,且安全性较高,可能与其明显改善患者血清G-17、ET-1、PG I、PG II、EGF及NO水平有关。