Origin and mediation of secretion induced by oral phytohaemagglutinin (PHA) in rats.
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After oral administration several gut-binding lectins induce accumulation of liquor and amylase in the proximal small intestine. Orally administered Phaseolus vulgaris phytohaemagglutinin (PHA) was used to study the mediation of these effects in rats. The regulation of amylase secretion clearly differed from that of the liquor. The amylase activity was of pancreatic origin, in agreement with the known cholecystokinin-releasing effect of PHA. It appears that CCK exerts its effect both directly and by facilitating neural stimulatory pathways. Intestinal secretion was identified as the source of the liquor, without a contribution by other secretions. It was mediated by a local cholinergic reflex with the involvement of both muscarinic and nicotinic acetylcholine receptors. It is speculated that the observed enteric reflex may enable the gut to transport secreted antibacterial peptides or secretory antibodies from the crypts to adherent bacteria on adjacent villi. (+info)
Lanthanum inhibition of Vibrio cholerae and Escherichia coli enterotoxin-induced enterosorption and its effects on intestinal mucosa cyclic adenosine 3',5'-monophosphate and cyclic guanosine 3',5'-monophosphate levels.
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Several trivalent cations, including lanthanum (La3+), inhibited the secretion (enterosorption) induced by the enterotoxins of Vibrio cholerae and Escherichia coli in the rabbit ileum in vivo. High concentrations (greater than 10 mM) of La3+ were required to inhibit cholera enterotoxin (CE)-induced enterosorption, probably because of the adsorption of the La3+ often potentiated the CE-induced enterosorption. If luminal La3+ exposure followed CE exposure, some recovery of the enterosorptive response was observed. The longer the lag between the CE exposure and the La3+ exposure, the greater was the recovery of the enterosorptive response. Lanthanum inhibited HCO3- secretion more than Cl- secretion. By altering the luminal fluid pH at the time of La3+ exposure, it was found that La3+ was adsorbed to negatively charged luminal sites, having an apparent pK between 2.5 and 3.0. Although La3+ antagonized the enterosorptive response to CE, it mimicked rather than antagonized the cyclic adenosine 3',5'-monophosphate elevation and cyclic guanosine 3',5'-monophosphate depression induced by the toxin. It is therefore concluded that the La3+ inhibition of the CE-induced enterosorption must have occurred at a site following the generation of the cyclic nucleotides. Cholera enterotoxin caused complex time-dependent changes in the mucosal cyclic adenosine 3',5'-monophosphate and cyclic guanosine 3',5'-monophosphate levels, as revealed by studying tissue cyclic adenosine 3',5'-monophosphate/cyclic guanosine 3',5'-monophosphate ratios. The possible roles these two cyclic nucleotides may play in the pathogenesis of the cholera diarrhea are discussed. (+info)
Immunosenescence and mucosal immunity: significant effects of old age on secretory IgA concentrations and intraepithelial lymphocyte counts.
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Concentrations of immunoglobulins (Ig) and levels of isotype specific antibodies to three dietary antigens in serum, pure parotid saliva, and in intestinal secretions obtained by whole gut lavage from groups of healthy elderly subjects (aged greater than 70 years) and of younger adult controls (aged 25-50 years) were measured. In addition, counts of lamina propria and intra-epithelial lymphoid cells were performed in histologically normal jejunal biopsy specimens from elderly and younger subjects. Elderly subjects had significantly higher concentrations of serum and salivary IgA and of salivary IgM (both, p less than 0.01), and of salivary IgA antibodies than did the younger subjects, but the amount of immunoglobulin and antibody in whole gut lavage fluid was similar in the two age groups. Jejunal biopsy specimen cell counts showed higher IgA plasma cell counts and lower intraepithelial lymphocyte counts in the elderly group (p less than 0.01), with similar counts of IgM and IgG plasma cells, eosinophils, and mast cells in the two groups. There is evidence of significant effects of old age on the mucosal immune system. (+info)
Methods to evaluate biliary excretion of drugs in humans: an updated review.
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Determining the biliary clearance of drugs in humans is very challenging because bile is not readily accessible due to the anatomy of the hepatobiliary tract. The collection of bile usually is limited to postsurgical patients with underlying hepatobiliary disease. In healthy subjects, feces typically are used as a surrogate to quantify the amount of drug excreted via nonurinary pathways. Nevertheless, it is very important to characterize hepatobiliary elimination because this is a potential site of drug interactions that might result in significant alterations in systemic or hepatic exposure. In addition to the determination of in vivo biliary clearance values of drugs, the availability of in vitro models that can predict the extent of biliary excretion of drugs in humans may be a powerful tool in the preclinical stages of drug development. In this review, recent advances in the most commonly used in vivo methods to estimate biliary excretion of drugs in humans are outlined. Additionally, in vitro models that can be employed to investigate the molecular processes involved in biliary excretion are discussed to present an updated picture of the new tools and techniques that are available to study the complex processes involved in hepatic drug transport. (+info)
Calcium-sensing receptor abrogates secretagogue- induced increases in intestinal net fluid secretion by enhancing cyclic nucleotide destruction.
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The calcium-sensing receptor (CaSR) provides a fundamental mechanism for diverse cells to detect and respond to modulations in the ionic and nutrient compositions of their extracellular milieu. The roles for this receptor are largely unknown in the intestinal tract, where epithelial cells are normally exposed to large variations in extracellular solutes. Here, we show that colonic CaSR signaling stimulates the degradation of cyclic nucleotides by phosphodiesterases and describe the ability of receptor activation to reverse the fluid and electrolyte secretory actions of cAMP- and cGMP-generating secretagogues, including cholera toxin and heat stable Escherichia coli enterotoxin STa. Our results suggest a paradigm for regulation of intestinal fluid transport where fine tuning is accomplished by the counterbalancing effects of solute activation of the CaSR on neuronal and hormonal secretagogue actions. The reversal of cholera toxin- and STa endotoxin-induced fluid secretion by a small-molecule CaSR agonist suggests that these compounds may provide a unique therapy for secretory diarrheas. (+info)
Manipulation of intestinal immune responses against ovalbumin by cholera toxin and its B subunit in mice.
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We studied the effect of mucosal presentation of ovalbumin (OVA) conjugated to cholera toxin (CT) or cholera toxin B subunit (CTB) on the intestinal immune responses against OVA. Mice were primed intraperitoneally (i.p.) with OVA in a water-in-oil emulsion and boosted intraduodenally (i.d.) with OVA conjugated to CT or CTB in various molar ratios. Responses were evaluated by testing intestinal secretions for OVA-specific antibodies and by quantifying the OVA-specific antibody secreting cells (ASC) in the lamina propria of the small intestine. OVA-CT conjugates were tested in a molar ratio ranging from 1.8:1 to 4500:1. OVA-CTB conjugates were tested in a molar ratio ranging from 0.25:1 to 500:1. The optimum intestinal immune response was reached at a molar ratio of 1.8:1 for OVA-CT and 5:1 for OVA-CTB. The binding capacity of OVA-CTB, but not of OVA-CT, to GM1 ganglioside corresponded with the capacity to enhance the intestinal immune response. The effect of conjugating CTB or CT to OVA on the immune response against OVA was more striking when mice were not only boosted i.d., but also primed i.d. Both OVA-CT and OVA-CTB induced detectable immune responses, whereas free OVA did not. Therefore, the carrier effect of CT or CTB is essential to trigger a mucosal immune response against OVA when presented mucosally only. We conclude that enhancing antigen uptake greatly facilitates mucosal immune responses. (+info)
Tin protoporphyrin induces intestinal chloride secretion by inducing light oxidation processes.
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Heme induces Cl(-) secretion in intestinal epithelial cells, most likely via carbon monoxide (CO) generation. The major source of endogenous CO comes from the degradation of heme via heme oxygenase (HO). We hypothesized that an inhibitor of HO activity, tin protoporphyrin (SnPP), may inhibit the stimulatory effect of heme on Cl(-) secretion. To test this hypothesis, we treated an intestinal epithelial cell line (Caco-2 cells) with SnPP. In contrast to our expectations, Caco-2 cells treated with SnPP had an increase in their short-circuit currents (I(sc)) in Ussing chambers. This effect was observed only when the system was exposed to ambient light. SnPP-induced I(sc) was caused by Cl(-) secretion because it was inhibited in Cl(-)-free medium, with ouabain or 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). The Cl(-) secretion was not via activation of the CFTR, because a specific inhibitor had no effect. Likewise, inhibitors of adenylate cyclase and guanylate cyclase had no effect on the enhanced I(sc). SnPP-induced I(sc) was inhibited by the antioxidant vitamins, alpha-tocopherol and ascorbic acid. Electron paramagnetic resonance experiments confirmed that oxidative reactions were initiated with light in cells loaded with SnPP. These data suggest that SnPP-induced effects may not be entirely due to the inhibition of HO activity but rather to light-induced oxidative processes. These novel effects of SnPP-photosensitized oxidation may also lead to a new understanding of how intestinal Cl(-) secretion can be regulated by the redox environment of the cell. (+info)
Acute inflammation alters bicarbonate transport in mouse ileum.
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T-cell mediated acute inflammation of the ileum may occur during Crohn's disease exacerbations. During ileal inflammation, absorption of nutrients and electrolytes by villus cells is decreased with a concomitant increase in crypt and/or villus fluid secretion. These alterations lead to fluid accumulation and the subsequent diarrhoea. Net intestinal fluid secretion consists of HCO3--rich plasma-like fluid. However, the regulation and mechanisms of HCO3- secretion in normal and acutely inflamed ileum are not clearly understood. To study this phenomenon, anti-CD3 monoclonal antibody (mAb)- induced in vivo ileal inflammatory mouse models was used for in vitro functional studies with Ussing chamber and pH stat techniques. Three hours after anti-CD3 mAb injection, ileal mucosa stripped of muscular and serosal layers showed a significant increase in short circuit current (Isc) (0.58+/-0.07 microEq h(-1) cm2 versus 1.63+/-0.14 microEq h(-1) cm2). The cAMP-stimulated Isc component was sensitive to glibenclamide but not to DIDS, suggesting that a cystic fibrosis transmembrane conductance regulator (Cftr)-mediated anion conductance was responsible. Basal Cl--dependent HCO3- secretion, measured using a pH stat technique, was decreased significantly in anti-CD3-injected mice, with a simultaneous increase in Cl--independent HCO3- secretion that was also inhibited by glibenclamide. Experiments using Cftr-/- mice showed neither an increase in Isc nor an increase in HCO3- secretion, confirming the role for Cftr protein in stimulating anion secretion following anti-CD3 treatment. Western blot analysis indicated that Cftr protein levels were unaltered by anti-CD3 treatment, at least acutely. Finally, an immunoassay for cAMP showed significant increases in intracellular cAMP in villus cells, but not in crypt cells. These studies therefore suggest a shift from a predominantly electroneutral Cl-HCO3- exchange in normal mice, to a predominantly electrogenic anion secretion including HCO3- that occurs via functional Cftr during anti-CD3-mediated acute inflammation. (+info)