Digestion

Blum, Hubert E.; Wieland, Stefan; von Weizsäcker, Fritz

doi: 10.1159/000201429pmid: 9144296

Molecular analyses have become an integral part of biomedical research as well as clinical medicine. The definition of the molecular and genetic basis of many human diseases has led not only to a better understanding of their pathogenesis, but has in addition offered new perspectives for their diagnosis, therapy, and prevention. Genetically, human diseases can be classified as monogenetic, complex genetic, and acquired genetic diseases. Based on this genetic classification, gene therapy involves four concepts: gene substitution, gene augmentation, block of gene expression or function as well as somatic transgene vaccination. Despite exciting recent developments, various delivery, targeting, and safety aspects need to be addressed before gene therapy will enter clinical practice. Clearly, molecular diagnosis and gene therapy of gastrointestinal diseases will be increasingly part of our patient management, complementing existing diagnostic, therapeutic, and preventive strategies.

Carroccio, A.; Iovanna, J.L.; Iacono, G.; Li Pani, M.; Montalto, G.; Cavataio, F.; Marasà, L.; Barthellémy-Bialas, S.; Dagorn, J.C.

doi: 10.1159/000201430pmid: 9144297

Since PAP is a stress protein expressed in human pancreas during pancreatitis but also constitutively synthesized in the small intestine, we looked whether its expression would be altered in patients with celiac disease. Serum PAP concentrations were determined consecutively in 54 patients with celiac disease on a free diet (group A), in 47 patients with celiac disease on a gluten-free diet (group B), in 22 patients with other intestinal pathologies but with normal intestinal mucosa (group C), in 14 patients with retarded growth, no gastrointestinal disease and normal intestinal mucosa (group D), and in 17 controls (group E). Serum PAP levels (ng/ml) were significantly higher in group A (127.3 ± 56.8) than in the other groups (B: 47.2 ± 20.5; C: 51.5 ± 32.2; D: 47 ± 22.8; E: 27.6 ± 9.0), which were not different from each other. In group A, a positive correlation was observed between serum PAP values and antigluten antibody levels (vs. AGA IgG r – 0.58, p < 0.001; vs. AGA IgA r = 0.66, p < 0.001). Furthermore, 12 patients from group A were evaluated after 10-12 months of gluten-free diet and in all of them PAP serum concentration had decreased (mean ± SE before the diet 122.5 ± 36.4, after the diet 48.7 ± 13.7, p < 0.0001). In addition, we performed an immunocytochemical study to localize PAP in the intestinal mucosa of patients from all groups except E. PAP was localized to the Paneth cells and to some globet cells, in patients with mucosal atrophy as well as in those with normal mucosa with no obvious quantitative difference. We concluded that in patients with celiac disease the active phase of the disease was accompanied by an increased serum concentration of PAP. Further studies are necessary to understand the mechanism leading to PAP elevation in the serum of patients with celiac disease.

Miyasaka, Kyoko; Masuda, Masao; Funakoshi, Akihiro

doi: 10.1159/000201431pmid: 9144298

An Otsuka Long-Evans Tokushima Fatty (OLETF) rat does not possess cholecystokinin (CKK)-A receptor gene expression because of a genetic abnormality. We examined the CCK release and its transcription in OLETF rats in comparison with control (Long-Evans-Tokushima-LETO) rats. Animals at 5-6 and 24-25 weeks of age were used. The level of CCK mRNA and CCK concentration in the small intestinal mucosa, and the level of CCK-A receptor mRNA in the pancreas were examined. To examine CCK release, rats were prepared with external bile and pancreatic fistulae. The basal plasma levels of CCK and those at 2 h after bile-pancreatic juice diversion were measured by radioimmunoassay. The levels of CCK mRNA, and tissue CCK concentration increased significantly with age in both strains, but the values in OLETF rats were significantly lower than those in LETO rats. The CCK-A receptor mRNA level also increased with age in LETO rats. The plasma CCK concentration was significantly increased by bile-pancreatic juice diversion regardless of age and strain; however, the level of plasma CCK in OLETF rats at 24-25 weeks of age was significantly lower than that of LETO rats. It is suggested that the long-term defect of CCK-A receptor may decrease CCK release and transcription.

v. Schönfeld, J.; Hector, M.; Evans, D.F.; Wingate, D.L.

doi: 10.1159/000201432pmid: 9144299

The presence of acid in the oesophagus has been shown to stimulate salivary secretion, but the relevance of this oesophago-salivary reflex for acid clearance in physiological and pathological gastro-oesophageal reflux (GOR) is unknown. This study was designed to investigate the interrelation between oesophageal acid and both resting and stimulated salivary secretion. In 10 healthy volunteers, the acid clearance times after bolus infusion of 20 ml of 0.1 N hydrochloric acid were measured by means of ambulatory oesophageal pH monitoring. With a constant swallowing rate and resting salivary flow, the acid clearance time was significantly longer with dry as opposed to wet swallows (12.6 ± 2.6 vs. 6.9 ± 1.9 min; p = 0.01). When the salivary flow was doubled by chewing a gum base (26.0 ± 3.4 vs. 13.2 ± 2.0 ml/l5 min; p = 0.005), the acid clearance time was markedly shortened (6.9 ± 1.9 vs. 2.3 ± 0.2 min; p = 0.02). As compared with water control, salivary flow, pH, and protein content were not affected by a bolus infusion of hydrochloric acid. This was true both for resting and gum-stimulated salivary secretion. Our study suggests that an oesophago-salivary reflex becomes effective only in prolonged episodes of GOR. This may explain why the water brash phenomenon is not regularly experienced by all reflux patients. Our study also suggests that chewing gum might be a non-pharmacological treatment option for some patients with symptomatic GOR.

Klatt, S.; Pieramico, O.; Güthner, C.; Ditschuneit, H.H.; Glasbrenner, B.; Beckh, K.; Adler, G.

doi: 10.1159/000201433pmid: 9144300

The role of altered gastric motor functions for the development of obesity is still unclear. In this study, we investigated whether severe obesity is related to gastric dysfunctions or to abnormal perception in response to distension. 31 obese patients and 20 healthy volunteers were studied using an electronic barostat. Basal gastric tone, gastric accommodation, and perception in response to distension were not altered in obese patients. The median minimal distending pressure, reflecting the intra-abdominal pressure, was significantly elevated in obese patients, being 12 versus 7 mm Hg, respectively (p < 0.0001). We conclude that the proximal gastric motility, including perception and accommodation in response to intragastric distension, is not impaired in severe obesity. Whether disturbances of gastric reflex relaxation in response to a meal are involved in the pathogenesis of obesity remains to be established.

Tominaga, Kazunari; Arakawa, Tetsuo; Tanaka, Miho; Fukuda, Takashi; Kim, Shokei; Iwao, Hiroshi; Kobayashi, Kenzo

doi: 10.1159/000201434pmid: 9144301

This study was done to investigate the gene expression and localization of tenascin in ulcerated gastric tissues during the healing process with Northern blot analysis and immunohistochemical technique. Gastric ulcers in rats were produced by acetic acid. Tenascin mRNA levels in the ulcerated tissue were significantly increased in a biphasic manner (12 h and day 5), preceding the increase in collagen type IV and laminin mRNA levels, and returned to control levels on day 11. In intact tissues, tenascin was mainly localized in the basement membrane above the proliferative zone, in contrast to the predominant localization of collagen type IV and laminin below the proliferative zone. On the ulcer margin from 12 h to day 5, tenascin was abundantly observed in the lamina propria around nonproliferating new epithelial cells, but collagen type IV and laminin were not seen in this lamina propria. On day 7, tenascin, expressed in the lamina propria, was replaced by collagen type IV and laminin. Thus, the rapid expression and unique localization of tenascin suggest the important role of tenascin in gastric ulcer healing.

Al Moutaery, Ahmed R.; Tariq, M.

doi: 10.1159/000201435pmid: 9144302

Quinacrine, a phospholipase A₂ inhibitor, has been studied for its ability to inhibit gastric secretion and to protect the gastric and duodenal mucosa against chemically and stress-induced ulcers. Acid secretion studies were undertaken in pylorus-ligated rats with and without quinacrine treatment. Experimental gastric lesions were induced by water-immersion restraint stress, indomethacin and 80% ethanol in rats; whereas duodenal ulcers were produced by treatment of rats with cysteamine. The level of nonprotein sulfhydryl compounds and gastric wall mucus were also measured in the glandular stomach of the rats following ethanol-induced gastric lesions. The results of this study demonstrate that quinacrine produces a dose-dependent inhibition of gastric acid secretion in rats. Pretreatment with quinacrine significantly attenuated the formation of stress-, indomethacin- and ethanol-induced gastric lesions. Quinacrine also protected intestinal mucosa against cysteamine-induced duodenal ulcers. The antiulcer activity of quinacrine was associated with appreciable inhibition of ethanol-induced depletion of nonprotein sulfhydryls and gastric wall mucus. These findings point towards the mediation of sulfhydryls in quinacrine-induced gastrointestinal cytoprotection. In conclusion, this study demonstrates that quinacrine possesses significant antiulcer and cytoprotective activity against various experimentally induced gastroduodenal lesions. Although the mechanism of action of quinacrine requires further evaluation, the experimental observations derived from this study may have future clinical relevance and therefore deserve to be investigated thoroughly.

Mall, Anwar S.; Merrifield, Edwin; Fourie, Joan; McLeod, Heather; Hickman, Rosemary

doi: 10.1159/000201436pmid: 9144303

Bile duct ligation in the pig results in ulceration of the pars oesophagea (oesophagogastric junction) within 48 h with 100% reproducibility. This work describes novel observations made during development of such ulcers using an endoscope introduced at intervals postoperatively via a Thomas gastric cannula. Macroscopic and histological changes were recorded and compared with quantitative and qualitative changes in crude mucus scrapings and purified mucins. Crude mucus scrapings of the cardiac gland region had a higher protein content in the ulcerated states than in the normals. After bile duct ligation, the (degraded) mucin glycopeptide/total protein ratio was higher in partially purified mucus from pre-ulcerated and ulcerated stomachs as compared with normal samples. The quantity of purified mucin was less in samples from ulcerated stomachs, and the N-acetylgalactosamine and fucose contents were also decreased. It is possible that these changes resulted in the failure of the mucus barrier and the development of oesophagogastric junction ulceration.

Blank, Marion A.; Ems, Beth L.; O’Brien, Linda M.; Weisshaar, Pamela S.; Ares, Jeffrey J.; Abel, Peter W.; McCafferty, Donna-Marie; Wallace, John L.

doi: 10.1159/000201437pmid: 9144304

To elucidate the mechanisms of flavonoid-induced protection against nonsteroidal anti-inflammatory drug (indomethacin)-induced acute gastric damage, the effects of 5-methoxyflavone and 5-methoxyflavanone on the gastric vascu-lature were compared both in vivo (using laser Doppler flowmetry in anesthetized rats) and in vitro on rat superior mesenteric arteries. The effects of the compounds on indomethacin-induced leukocyte adherence to mesenteric venules were investigated by intravital videomicroscopy. Oral 5-methoxyflavone reduced indomethacin-induced macroscopic damage by 38 to 99% (ED₅₀ = 5.5 mg/kg). Damage was not significantly reduced by 5-methoxyflavanone. Light microscopy studies also demonstrated a reduction in damage severity. 5-Methoxyflavone, but not 5-methoxyflavanone, increased the gastric conductance significantly. The effects on isolated mesenteric arteries correlated with the effects on in vivo conductance. Finally, indomethacin-induced leukocyte adherence was inhibited to a greater extent by 5-methoxyflavone than by 5-methoxyflavanone. In conclusion, the flavonoid 5-methoxyflavone provides gastroprotection against nonsteroidal anti-inflammatory drug-induced gastric damage. A structurally similar compound, 5-methoxyflavanone, demonstrated minimal gastroprotective activity, suggesting that the double bond of 5-methoxyflavone is required for biological activity. The finding that 5-methoxyflavone (but not 5-methoxyflavanone) significantly increased gastric vascular perfusion and reduced leukocyte adherence to mesenteric venules suggests that these mechanisms may contribute to the flavonoid’s gastroprotective activity.

Bailey, David; Turnbull, George; Bartsch, Richard; Begent, Richard; Sapsford, Richard; Ciclitira, Paul J.

doi: 10.1159/000201438pmid: 9144305

The aim was to study the development of human small intestinal microvillus membranes. We compared the protein patterns of human fetal and adult small intestinal microvillus membranes using the high-resolution technique of sodium dodecyl sulphate-polyacrylamide gel electrophoresis. We also examined the synthesis of brush border membrane proteins from the adult small intestine using small intestinal biopsy organ culture ³⁵S-methionine uptake and subsequent gel electrophoresis. We observed that the fetal and colonic microvillus membranes were similar, but differed in certain respects from adult small intestinal microvillus membranes. The jejunal biopsy organ culture revealed that synthesised brush border membrane proteins could be recognized by gel electrophoresis.