Effect of gastrointestinal secretions on the formation of hemorrhagic intestinal necrosis in Escherichia coli endotoxin shock.
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Enteric nervous system: intestinal absorption and secretion.
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Humans↗
Diseases of intestinal absorption and secretion.
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Humans↗
[Phospholipid secretion in the large and small intestines of dogs].
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Animals↗
Brain vasoactive intestinal peptide: a potent stimulant of gastric acid secretion.
Vasoactive intestinal peptide (VIP) belongs to a rapidly expanding family of cerebrogastrointestinal oligopeptides. This report describes a potent dose-, time- and vagus-dependent stimulation of gastric acid secretion by brain VIP. Physiologic evidence favoring a role of VIP on acid secretion was provided by the finding that immunoneutralization of endogenous brain VIP produced a significant decrease of acid secretion. These and other data contained herein suggest that the mechanism by which central VIP stimulates acid secretion appears to involve peripheral cholinergic pathways.
Animals↗
Secretory effect of azodisalicylate (azodisal sodium) on the short circuited mucosa of the rat ileum in vitro.
Azodisalicylate (ADS) is one of the newly developed substitutes of sulphasalazine consisting of two molecules of 5-amino-salicylic acid. Azodisalicylate caused diarrhoea in some patients, apparently caused by an antiabsorptive secretagogue action of this compound. The mechanism of this was studied in the short circuited isolated mucosa of the rat ileum. Mucosal addition of ADS increased the potential difference (PD) and short circuit current (Isc) at a concentration of 1.3.10(-4) mol/l (4 mg/dl) with maximal effects at 1.3.10(-3) mol/l (40 mg/dl). Epithelial resistance was only slightly decreased at the higher concentrations of 40 and 100 mg/dl. Serosal ADS had no effect on electrical parameters. The increase of Isc was associated with a change of net chloride absorption into net secretion. Net sodium absorption was only slightly and not significantly decreased. The changes were reversible after rinsing away the ADS. Treatment of the mucosa with furosemide inhibited the ADS induced increase of Isc, suggesting transcellular pathway for the ADS stimulated secretion. Biosynthesis of prostaglandins is not involved in the mechanism of this secretion, as treatment with indomethacin did not alter the effect of ADS on Isc. Results suggest that ADS can be considered as a secretagogue, which stimulates intestinal secretion via a transcellular pathway. Because of the bacterial cleavage of the double molecule into two molecules of the non-secretagogue 5-amino-salicylic acid in the colon, however, diarrhoea may develop only in patients with a decreased absorptive capacity of the colon, or insufficient cleavage of ADS.
Aminosalicylic Acids↗
Cholinergic mechanisms in intestinal phase insulin secretion in rats.
The present study was designed to examine the role of neural cholinergic mechanisms in intestinal phase insulin secretion during increasing intraduodenal instillation rates of the test meals. In groups of 12 anesthetized rats arterial insulin levels rose significantly in relation to the increase of the rate at which the liver extract/sucrose was instilled intraduodenally (0.15, 0.5 and 1.5 ml/min). The injection of atropine (10 micrograms/kg) 5 min prior to the intraduodenal infusion of the test meals abolished this rate-dependent augmentation of insulin levels completely. Similarly, no effect of increasing intraduodenal infusion rates of the meal was observed in islet-transplanted rats. These data demonstrate that neural - at least in part muscarinic cholinergic - mechanisms participate in intestinal phase insulin secretion of rats supporting previous observations about the importance of neural factors in the regulation of postprandial insulin release.
Acetylcholine↗
Impaired gastric function in experimental malnutrition.
Selective dietary protein deprivation led to impaired pentagastrin stimulated gastric acid secretion in rats but was not simply due to lower body weights in the experimental group. This may be a significant pathophysiological factor in clinical malnutrition because of reduction of gastric acid control over bacterial populations in upper intestinal secretions.
Animals↗
Oral immunization with a free peptide from cholera toxin: local protection and IgA production.
It is frequently of great benefit for good protection against pathogens to elicit a local immunization. For example the importance of antibacterial as well as antitoxin local secretory IgA, for protection against cholera, has been underlined in several studies. We have already reported that oral administration of the peptide corresponding to the 50-75 sequence of cholera toxin (CT) B subunit elicits serum antibodies neutralizing CT activity. In this study we demonstrate that IgA with specificity to CT are present in intestinal secretions of mice immunized orally with the P50-75 or P30-50 peptides of CT B subunit. In addition local protection is observed in the intestine of P50-75 orally immunized mice. These results point out the potential of synthetic peptides as immunogens at the mucosal level.
Administration, Oral↗
The antifungal antibiotic, clotrimazole, inhibits chloride secretion by human intestinal T84 cells via blockade of distinct basolateral K+ conductances. Demonstration of efficacy in intact rabbit colon and in an in vivo mouse model of cholera.
The antifungal antibiotic clotrimazole (CLT) blocks directly and with high potency the Ca2+-activated K+ channels of human erythrocytes, erythroleukemia cells, and ferret vascular smooth muscle cells. We recently reported that CLT inhibits Cl- secretion in human intestinal T84 cells, likely by affecting K+ transport (Rufo, P.A., L. Jiang, S.J. Moe, C. Brugnara, S.L. Alper, and W.I. Lencer. 1996. J. Clin. Invest. 98:2066-2075). To determine if CLT had direct effects on K+ conductances in T84 cells, we selectively permeabilized apical membranes of confluent T84 cell monolayers using the ionophore amphotericin B. This technique permits direct measurement of basolateral K+ transport. We found that CLT and a stable des-imidazolyl derivative inhibited directly two pharmacologically distinct basolateral membrane K+conductances, but had no effect on apical membrane Cl- conductances. The effects of CLT on Cl- secretion were also examined in intact tissue. CLT inhibited forskolin-induced Cl- secretion in rabbit colonic mucosal sheets mounted in Ussing chambers by 91%. CLT also inhibited cholera toxin-induced intestinal Cl- secretion in intact mice by 94%. These data provide direct evidence that CLT blocks Cl- secretion in intestinal T84 cells by inhibition of basolateral K+ conductances, and show that CLT inhibits salt and water secretion from intact tissue in vitro and in vivo. The results further support the suggestion that CLT and its metabolites may show clinical efficacy in the treatment of secretory diarrheas of diverse etiologies.
Animals↗
Role of 5-hydroxytryptamine type 3 receptors in rat intestinal fluid and electrolyte secretion induced by cholera and Escherichia coli enterotoxins.
Cholera toxin and Escherichia coli heat labile toxin (LT) induced intestinal secretion has in the past been attributed exclusively to an increase in intracellular cAMP whereas E coli heat stable toxin (ST) induced secretion is mediated through cGMP. Evidence is accumulating on the importance of 5-hydroxytryptamine (5-HT) in cholera toxin induced secretion, but its role in LT and ST is not well established. This study therefore investigated in vivo the effect of 5-HT3 receptor antagonist, granisetron, on intestinal fluid and electrolyte secretion induced by cholera toxin, LT, and ST. Granisetron (30, 75, 150, or 300 micrograms/kg) was given subcutaneously to adult male Wistar rats 90 minutes before instillation of 75 micrograms cholera toxin or 50 micrograms LT in isolated whole small intestine. In situ small intestinal perfusion was performed with an iso-osmotic plasma electrolyte solution (PES) to assess fluid movement. In a second group of animals, granisetron (300 micrograms/kg) was given subcutaneously and two hours later small intestinal perfusion with PES containing 200 micrograms/l ST was performed. Cholera toxin induced net fluid secretion (median -50.1 microliters/min/g (interquartile range -59.5 to -29.8)) was found to be dose dependently decreased or abolished by granisetron (plateau effect at 75 micrograms/kg: 18 (-7.8 to 28), p < 0.01). Granisetron in high dose (300 micrograms/kg), however, failed to prevent LT or ST induced secretion (-52 (-121 to -71) v -31 (-44 to -18), and (-39 (-49 to 17) v (-22 (-39 to -3)), respectively). Sodium and chloride movement paralleled that of fluid. In conclusion, these data show that 5-HT and 5-HT3 receptors play an important part in cholera toxin induced secretion but are not involved in E coli heat stable or heat labile toxin induced secretion.
Animals↗
Diversion or prevention of biliary outflow from the liver diminishes the renal uptake of injected inorganic mercury.
In the present study, we tested the hypothesis that diversion of biliary flow from the liver to the intestines (using biliary cannulation) or prevention of biliary outflow from the liver ( by biliary ligation) affects significantly the renal uptake and accumulation of mercury in rats given an intravenous nontoxic (0.5 mumol/kg) dose of mercuric chloride (containing 203 HgCl2). Diverting biliary flow away from the small intestine, by cannulation of the bile duct, caused a significant increase in the content of mercury in the blood and caused a significant decrease in the total renal uptake of mercury at 1 and 3 hr after the injection of mercuric chloride. By the end of 3 hr after the injection of mercury, the amount of mercury that was not taken up by the kidneys, as a result of diversion of biliary flow, was approximately 10% of the administered dose. The decreased renal uptake of mercury was caused by decreased uptake of mercury in the renal cortex and outer stripe of the outer medulla. Interestingly, very little mercury was excreted in the bile. Only approximately 0.19% of the administered dose of mercury was excreted in the bile in 3 hr. Renal accumulation of mercury, particularly in the cortex and outer stripe of the outer medulla, was also reduced significantly after biliary ligation, when evaluated 24 hr after the injection of inorganic mercury. There was an almost 3-fold increase in the content of mercury in the liver of the rats whose bile duct had been ligated. Fecal excretion of mercury was also diminished in these animals. It was interesting, however, that these rats did excrete some mercury in the feces. Dispositional data obtained from the segments of the gastrointestinal tract indicate that fecal excretion of mercury in the rats whose bile duct had been ligated was most likely caused by intestinal secretion of mercury. In conclusion, the present findings indicate that a hepato-biliary-enteric metabolic pathway plays a role in some aspect of the renal accumulation of administered inorganic mercury. This role does not, however, seem to involve, to any significant degree, the biliary and enteric processing of mercury secreted into the bile.
Animals↗
Molecular cloning of GRA4, a Toxoplasma gondii dense granule protein, recognized by mucosal IgA antibodies.
Clones which were selected from a Toxoplasma gondii expression library with the immune serum from a T. gondii-infected rabbit, were further screened using milk and intestinal secretions from mice which had been orally infected with T. gondii cysts. The gene products of several clones reacted strongly with milk IgA and weakly with intestinal IgA. Three of these clones (5.1, 36.1, 37.4) were shown to encode a dense granule protein of 40 kDa (GRA4). The GRA4 protein co-migrates with one of the T. gondii antigens recognized by mucosal IgA. The complete nucleotide sequence of GRA4 has been obtained by cloning genomic T. gondii BamHI fragments containing the 37.4 DNA insert. The coding sequence contains no intron. The deduced amino acid sequence indicates a proline rich (12%) product with an internal hydrophobic region of 19 amino acids and a potential site of N-glycosylation. The primary translation product with a theoretical size of 36,260 Da contains a putative N-terminal signal sequence of 20 amino acids but no apparent glycolipid anchor sequence. Quantitation of the GRA4 gene and Southern blot analysis suggested that the GRA4 gene is single copy. GRA4 gene is translated in tachyzoites to yield a single mRNA species of about 1900 bases.
Amino Acid Sequence↗
Impaired mucosal defense to acute colonic injury in mice lacking cyclooxygenase-1 or cyclooxygenase-2.
To investigate roles in intestinal inflammation for the 2 cyclooxygenase (COX) isoforms, we determined susceptibility to spontaneous and induced acute colitis in mice lacking either the COX-1 or COX-2 isoform. We treated wild-type, COX-1(-/-), COX-2(-/-), and heterozygous mice with dextran sodium sulfate (DSS) to provoke acute colonic inflammation, and we quantified tissue damage, prostaglandin (PG) E(2), and interleukin-1beta. No spontaneous gastrointestinal inflammation was detected in mice homozygous for either mutation, despite almost undetectable basal intestinal PGE(2) production in COX-1(-/-) mice. Both COX-1(-/-) and COX-2(-/-) mice showed increased susceptibility to a low-dose of DSS that caused mild colonic epithelial injury in wild-type mice. COX-2(-/-) mice were more susceptible than COX-1(-/-) mice, and selective pharmacologic blockade of COX-2 potentiated injury in COX-1(-/-) mice. At a high dose, DSS treatment was fatal to 50% of the animals in each mutant group, but all wild-type mice survived. DSS treatment increased PGE(2) intestinal secretion in all groups except COX-2(-/-) mice. These results demonstrate that COX-1 and COX-2 share a crucial role in the defense of the intestinal mucosa (with inducible COX-2 being perhaps more active during inflammation) and that neither isoform is essential in maintaining mucosal homeostasis in the absence of injurious stimuli.
Animals↗
Adenylate cyclase in intestinal crypt and villus cells: stimulation by cholera enterotoxin and prostaglandin E1.
The secretory responses to cholera enterotoxin and prostaglandin E1 (PGE1) are dependent upon elevation of the intracellular levels of cyclic AMP. Although several previous reports have suggested that intestinal secretion due to cholera enterotoxin and PGE1 may be confined to the crypt cells, this matter has been incompletely resolved. These studies were undertaken to define the activity of adenylate cyclase in villus and crypt cells from rabbit and rat intestine, and to determine the influence of enterotoxin and PGE1 on this activity, Mucosal fractions were prepared from rabbit ileum with a planing device, and from rat distal small intestine by a vibration technique. In both species base line adenylate cyclase activity was greater in crypt than in villus cells. After exposure to cholera enterotoxin in vivo, adenylate cyclase activity was enhanced in all fractions prepared from rabbit ileum, and the response was most marked in villus cells. Furthermore, adenylate cyclase in membranes prepared from both rat villus and crypt intestinal cells was responsive to the in vitro addition of PGE1. The results of these studies indicate that both villus and crypt cells contain one of the important components required for the cyclic AMP-mediated secretory response, namely, a cholera enterotoxin and PGE1-sensitive adenylate cyclase activity. Since an increased level of cyclic AMP alone may not be sufficient to evoke a secretory response, these studies do not clarify the extent to which each of these major cell types may participate in cyclic AMP-mediated secretion.
Adenylyl Cyclases↗
Interleukin (IL)-13 and IL-4 are potent inhibitors of IL-8 secretion by human intestinal epithelial cells.
Intestinal epithelial cells are able to produce soluble mediators that initiate or amplify inflammatory events in the intestinal mucosa. Interleukin (IL) -8 is suggested to be a cytokine playing a major role during the acute and chronic processes in inflammatory bowel disease (IBD). TH-2 cytokines have been described as down-regulating the inflammatory response. We analyzed the effects of IL-10, IL-13, and IL-4 on IL-8 secretion in intestinal epithelial cells. The human colonic epithelial cell line Caco-2 and freshly isolated intestinal epithelial cells were used. Cells were stimulated with IL-1beta after treatment with TH-2 cytokines. Levels of IL-8 were determined by employing enzyme-linked immunosorbent assay (ELISA). Stimulation with IL-1beta results in a time-dependent IL-8 secretion. The addition of IL-4 and IL-13, but not IL-10, to activated epithelial cells resulted in a strong decrease in IL-8 secretion. Maximal inhibition required that TH-2 cytokines be added up to 60 min before or simultaneous with stimulatory agents. We present novel findings that IL-4 and IL-13 strongly down-regulate IL-8 secretion from intestinal epithelial cells. A microenvironment containing high concentrations of IL-4 and IL-13 may alter the recruitment of immune cells to enterocytes at least partly by inhibiting IL-8 production. This inhibition might diminish the severity of the intestinal inflammatory response and, thus reduce clinical disease activity.
Caco-2 Cells↗
In vitro and ex vivo intestinal tissue models to measure mucoadhesion of poly (methacrylate) and N-trimethylated chitosan polymers.
PURPOSE: The adhesion of a range of polymers based on poly(2-(dimethylamino-ethyl) methacrylate (pDMAEMA) was assessed using human mucus-secreting and non mucus-secreting intestinal cell monolayers, HT29-MTX-E12 (E12) and HT29 monolayers, as well as excised non-everted intestinal sacs from rats. Differentiation of mucoadhesion from bioadhesion was achieved by pre-treatment with the mucolytic agent, N-acetyl cysteine (NAC). Adherence of pDMAEMA polymers was compared to that obtained with the mucoadhesive, N-trimethylated chitosan (TMC). METHODS: The quantity of adherent coumarin 343-conjugated polymers to HT29, E12, and intestinal sacs was measured by fluorescence. Confocal laser scanning microscopy (CLSM), light microscopy, and fluorescent microscopy were used to provide direct evidence. Measurements of transepithelial electrical resistance (TEER), permeability to FITC-dextran 4000 (FD-4), and the release of lactate dehydrogenase (LDH) were used to assess potential cytotoxicity of polymers. RESULTS: Adherence of unquaternized and of 10%, 24%, and 32% methyl iodide-quaternized pDMAEMA polymers was measured in E12, HT29, and sacs. All pDMAEMA polymers showed significantly higher levels of adhesion to mucus (mucoadhesion) than to epithelium (bioadhesion). Colocalization of pDMAEMA with mucus was confirmed in E12 by microscopy. TMC showed equally high levels of mucoadhesion as unquaternized and 24% quaternized pDMAEMA, but displayed higher levels of bioadhesion. pDMAEMA-based polymers demonstrated lower levels of adherence to E12 and rat sacs in the presence of NAC, whereas adherence of TMC was unchanged. pDMAEMA significantly decreased the permeability of FD-4 across E12 monolayers and sacs and was less cytotoxic in E12 than in HT29. In contrast, TMC increased the permeability of FD-4 across E12 and sacs and was less cytotoxic in E12 than in HT29. CONCLUSIONS: Human mucus-producing E12 monolayers can be used to assess polymer mucoadhesion and give similar data to isolated rat intestinal sacs. pDMAEMA displayed similar levels of mucoadhesion and lower levels of bioadhesion than a chitosan derivative and it was not cytotoxic. pDMAEMA decreased FD-4 flux in the presence of mucus, whereas TMC increased it. The combination of mucus and methacrylate polymers appears to increase barrier function of the apical membrane.
Animals↗
Central nervous system action of TRH to influence gastrointestinal function and ulceration.
There is clear evidence in rats that TRH acts in the brain to stimulate gastric acid, pepsin, and serotonin secretion, mucosal blood flow, contractility, emptying, and ulceration through activation of parasympathetic outflow to the stomach (TABLE 3). A number of TRH analogues, including some devoid of TSH-releasing activity, mimic the effects of TRH. The most sensitive TRH sites of action to elicit gastric acid secretion and motility are located in the dorsal vagal complex and include the dorsal vagal, nucleus tractus solitarius, and nucleus ambiguus. The gastrointestinal tract is one of the most responsive visceral systems to the central effects of TRH, because doses in the range of 1-10 pmol in the dorsal vagal complex stimulate gastric function, whereas stimulation of cardiovascular and respiratory function on microinjection of the brainstem nuclei requires higher doses. Although fewer investigations have been carried out in other species, evidence from the available data clearly indicates that TRH acts in the brain to increase gastric secretion and motility in the rabbit, sheep, and cat. Lack of stimulation of gastric acid secretion after third ventricle injection in the dog may be related to species difference or to rapid degradation of the peptide before it reaches its site of action. TRH acts centrally to stimulate gastric function and also intestinal secretion, motility, and transit as reported mostly in rabbits (TABLE 3). TRH produces enteropooling and release of serotonin in portal blood, increases duodenal and intestinal contractility and colonic transit, and elicits diarrhea. All these effects were shown to be vagally mediated. Stimulation of intestinal motility and transit by central injection of TRH has been observed in rats and sheep. The biological activity of centrally injected TRH is well correlated with the presence of TRH immunoreactivity and receptors in the dorsal vagal complex containing afferent and efferent connections to the stomach. Moreover, endogenous release of brain TRH in rats mimics the stimulatory effect of centrally injected TRH on gastric function. Although the lack of a specific TRH antagonist has hampered assessment of the physiological role of TRH, converging neuropharmacological, neuroanatomical, and physiological findings support the concept that TRH in the dorsal vagal complex may play a physiological role in the vagal regulation of gastrointestinal function.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗