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Vasoactive intestinal polypeptide (VIP) is released into the portal circulation in large quantities by ischaemic bowel. In view of its known high concentration in the gut and potent vasoactive properties it may well be implicated in the pathogenesis of the serious haemodynamic changes produced by gut ischaemia.
In vivo kinetics of mucosal uptake of luminal 59Fe2+ by tied segments of normal mouse duodenum are characterised by a Km of approx. 100 microM and a Vmax of approx. 9 pmol/min per mg wet weight of intestine. These values were determined at pH 7.25 in the presence of excess sodium ascorbate. Studies with luminal Fe2+ concentrations of 100 microM reveal: uptake is relatively independent of ascorbate: Fe ratio and luminal pH and uptake is potently inhibited by 1 mM Co2+ or Mn2+ and large luminal NaCl concentrations but not by Ca2+. 3 days of hypoxia (0.5 atmospheres) yields no significant increase in subsequent total mucosal uptake by in vivo tied segments while uptake is significantly reduced by semi-starvation. Quantitative comparison of in vivo mucosal uptake with subsequent determination of isolated brush-border membrane 59Fe2+ transport in individual mice reveals a positive correlation (P less than 0.01) between the two parameters. These results, in conjunction with studies of isolated mouse duodenal brush-border membrane (Simpson, R.J. and Peters, T.J. (1985) Biochim. Biophys. Acta, 814, 381-388 and (1986) Biochim. Biophys. Acta 856, 109-114) suggest that the Fe2+ transport properties of isolated brush-border membrane are quantitatively adequate to explain in vivo mucosal uptake in normal and hypoxic mice at Fe2+ concentrations up to 100 microM.
The effect of vasoactive intestinal polypeptide (VIP) on the electrical activity of the smooth muscle of the guinea-pig taenia coli has been examined using the single sucrose gap apparatus. VIP usually caused a slowly developing, long-lasting membrane hyperpolarisation, although sometimes it reduced the frequency of spontaneous spike discharge without hyperpolarising the membrane. In contrast, non-adrenergic, non-cholinergic nerve stimulation initiated rapid membrane hyperpolarisation followed by post inhibitory excitation. In the presence of apamin, the VIP response was little affected, whereas the responses to non-adrenergic, non-cholinergic nerve stimulation were either markedly antagonised or reversed to membrane depolarisation. Consideration is given to the possible role of either VIP or ATP as the neurotransmitter responsible for the inhibitory junction potential elicited in the guinea-pig taenia coli in response to non-adrenergic inhibitory nerve stimulation.
Intestinal tissues of man, rat, mouse, guinea-pig and rabbit were preincubated with laxatives, homogenised, and incubated with [14C]arachidonic acid. After extraction into chloroform, the eicosanoids were separated by thin layer chromatography. Metabolism of [14C]arachidonic acid into prostaglandins (PGs), and the lipoxygenase products LTB4 and 5-HETE, was stimulated by ricinoleic acid (100 micrograms/ml) or phenolphthalein (100 micrograms/ml), and to a lesser extent by picosulphate (125 micrograms/ml) and sulfosuccinate (200 micrograms/ml). Mannitol (500 micrograms/ml) had no effect. Indomethacin (1 microgram/ml) inhibited the stimulation of PG formation. The dual pathway inhibitor BW755C (1 microgram/ml) reduced the formation of prostaglandins, LTB4 and 5-HETE. In some experiments on rat colon, prostanoids were separated from lipoxygenase products, characterised by their chromatographic mobility and quantitated (relative amounts PGE2 greater than PGF2 alpha greater than TXB2 greater than PGD2). Their formation was enhanced by ricinoleic acid (100 micrograms/ml) and inhibited by either indomethacin or BW 755C (1 microgram/ml). The present results indicate that mammalian isolated gut tissue can convert [14C]arachidonic acid into both cyclo-oxygenase and lipoxygenase products, and support the suggestion that eicosanoids may participate in the laxative effect of some secretagogues.
BACKGROUND/AIMS: Vasoactive intestinal polypeptide (VIP) modulates the immunoglobulin (Ig) synthesis in the peripheral blood of humans and in various lymphoid organs of other species. Because VIP receptors have been shown on lamina propria mononuclear cells (LPMC), the effects of graded doses of VIP on the in vitro Ig production by normal human LPMC was investigated. METHODS: Colonic LPMC were cultured with or without graded doses of VIP (1 pmol/L-1 mumol/L). The concentrations of Ig A, G, and M in the 12 days supernatants were quantitated by an enzyme-linked immunosorbent assay, and the effects of VIP were characterized by limiting dilution analysis (LDA). RESULTS: The addition of VIP was associated with a significant increase in the production of IgA, whereas IgG levels were significantly reduced. Both these effects were restricted to LPMC. LDA showed that the IgA-enhancing effect was associated with an increase in the number of IgA-producing precursor cells and with variation in the regulatory phenomena involved in IgA production. CONCLUSIONS: In humans, a major function of the mucosal immune system (i.e., the synthesis of IgA) is modulated by VIP. Data suggest that VIP may either act as an indirect switch factor or increase the clone size of pre-committed cells.
BACKGROUND/AIMS: The flow rate of fluid through the proximal small intestine varies widely under normal physiological conditions. The aim of this study was to assess the effect of changes in flow rate on the passive permeability of the aqueous paracellular pathway of the human jejunum. METHODS: Normal subjects were studied in vivo during constant perfusion of 30-cm loops of jejunum at flow rates of 5, 10, or 20 mL/min. The permeability ratio of L-xylose/urea was used to assess apparent permeability of the mucosa and to calculate the average pore radius of the aqueous pathway for passive diffusion. RESULTS: Increasing jejunal flow rate from 5 to 20 mL/min significantly decreased the L-xylose/urea permeability ratio from 0.35 to 0.23 and decreased average calculated pore radius of the diffusion pathway from 13 A to 8 A. CONCLUSIONS: Increases in flow rate in the normal physiological range decrease the estimated pore size of normal healthy jejunal mucosa. Because increasing flow rate is known to increase exposure of luminal fluid to the intervillus space, the results of this study are best explained by postulating that cells lining the sides of villi are less permeable than cells lining the villus tips.
Intestinal obstruction inhibits amino acid absorption. The inhibition, being dependent on the pathological changes of the absorptive epithelium, was considered as an index of injury and measured after varying periods of obstruction and after pretreatment with clindamycin, indomethacin, 16,16-dimethyl-PGE2 or arachidonic acid. A reduction in amino acid uptake was apparent after 2h of obstruction and was increasingly evident after 4, 6 and 18 h. During the late phase (after 6 h), inhibition was partly prevented by pretreatment with clindamycin, but the antibiotic was ineffective during the early phase (within the first 2 h). Bacterial colony counts of luminal contents of rats obstructed for 2 h, were not different from counts obtained in controls, but significantly lower than counts in rats that have been obstructed for 6 h. Pretreatment of rats with 16,16-dimethyl-PGE2 or with arachidonic acid prevented the early inhibitory effects of the obstruction. The findings suggest that the early inhibition in amino acid uptake may be related to metabolic changes that are correctable by the administration of 16,16-dimethyl-PGE2 or of arachidonic acid. The inhibition, during the late phase, is mainly related to an overgrowth of the enteric bacteria.
Vasoactive intestinal polypeptide (VIP), peptide histidine isoleucine (PHI), and helodermin stimulate electrogenic anion secretion in preparations of rat jejunum stripped of muscularis propria. Concentration-response curves to exogenously applied peptides yielded EC50 values of 12 nM, 12 nM and 100 nM for VIP, PHI and helodermin respectively. These secretory responses were most probably mediated via the same receptor population given that cross-desensitisation was observed between all 3 analogues. Four putative VIP antagonists, namely, two growth hormone releasing factors (GRF); [AcTyr1, D-Phe2]GRF-(1-29)-NH2 and [AcTyr1]hGRF-(1-40)-OH as well as [4Cl-D-Phe6,Leu17]VIP and VIP-(10-28) were tested for their ability to inhibit VIP induced electrogenic ion secretion. None of the above exhibited any intrinsic agonist activity nor were they competitive antagonists, although some inhibition was observed with [AcTyr1]hGRF-(1-40)-OH and VIP-(10-28). Their use as selective VIP antagonists is therefore limited in rat jejunal mucosa.
Acquired immunodeficiency syndrome (AIDS) is initiated by the attachment of the human immunodeficiency virus (HIV) to specific target cells. An octapeptide sequence contained within the envelope of HIV, peptide T, mediates the viral binding. Since there is a considerable structural homology between peptide T and VIP, it has been proposed that the VIP receptor may be the naturally occurring protein which provides the corresponding cellular attachment site. In three different models (rat intestinal epithelial cell membranes, rat liver plasma membranes and human colonic cells), we document the lack of interaction between peptide T and the VIP receptor. These observations would also exclude any pathophysiologic effect caused by the crossreactivity of peptide T or its analogues and these VIP receptors.
1. In the fowl, the small intestine is important for net absorption of Ca2+ and K+, but not for Na+ nor water (in this and several other species). 2. Net water absorption in birds with large saccate caeca occurs in caeca greater than rectum greater than coprodeum, but net Na+ absorption (an active process motivating other absorptive functions) occurs in rectum less than caeca and coprodeum. 3. Interspecific variability and the scarcity of comparative studies militate against broad, well-founded generalisations in this subject.
1. DNA-synthesis was found to be gradually reduced in the intestinal crypt cells of ground squirrel during autumn at the time of preparation for hibernation and gradually rose during late hibernation season in February-March at the time of preparation for arousal. 2. A conclusion is made on the seasonal variations in cell replacement of true hibernators.
Calprotectin levels were measured by ELISA in plasma, terminal small bowel lavage and bronchoalveolar lavage from 8-day-old germ-free piglets or gnotobiotic piglets 24 h after colonization with one of the following Escherichia coli strains: non-pathogenic O86, probiotic Nissle 1917 or enteropathogenic O55. The concentration of calprotectin in plasma was about 30 ng/ml only in germ-free piglets and piglets associated with non-pathogenic E. coli. Piglets infected with O55 showed a significant increase of plasma calprotectin and the highest mean level of calprotectin in the bronchoalveolar lavage, which was coincident with septicaemia. However, in the lumen of the small intestine, E. coli Nissle 1917 alone elicited a significant increase of the calprotectin level which was confirmed by immunofluorescence and APAAP immunohistochemistry on cryostat sections through the small bowel. The relevance of this finding to the therapeutic effect of E. coli Nissle 1917 in inflammatory bowel disease is discussed.
Vasoactive intestinal polypeptide (VIP)-receptor mRNA was strongly expressed in the acinar cells in the submandibular gland but not in the sublingual gland. VIP-containing nerve fibres were richly distributed around acini in the submandibular gland but were rare around acini of the sublingual gland. In the submandibular gland, the chorda was stimulated at various frequencies (1-40 Hz) together with an infusion of (N-Ac-Tyr1, D-Phe2)-GRF(1-29)-NH2 (109 M), VIP antagonist, which reduced salivary flow from the submandibular gland only at high-frequency stimulation (> 20 Hz), and more markedly reduced the salivary protein concentration. When the chorda was continuously stimulated the antagonist reduced the salivary flow only during the initial 5 min. Exogenous VIP 10(-12) - 10(-8) M) infusion at the same time as chorda stimulation caused no increase in salivary flow, but the salivary protein concentration was increased in a dose-dependent manner. In the sublingual gland, neither VIP nor the VIP antagonist affected chorda-evoked salivary flow and protein concentration. Thus, endogenous VIP may play a part in the regulation of both fluid and protein secretion, especially of protein, evoked by chorda stimulation at high frequency in the submandibular gland. These phenomena occurred only in the initial phase of secretion. In the sublingual gland, it seems likely that VIP plays no part in the regulatory mechanism, at least with regard to salivary fluid secretion in the acinar cells.
To assess the gamma delta TCR T cells in the control of the timing of the mucosal response to enteric parasitic infections, we used C57BL mice, orally infected with 200 viable T. spiralis larvae. The small intestine, spleens and Peyer's patches (PP) were excised on 1, 4, 7, 14, 21 and 29 postinfection days (p.i.) for immunophenotyping and histological studies. Uninfected mice served as control. Characterization of isolated lymphocytes of C57BL control mice, confirmed that T cell immunophenotype differs in spleen, PP and i-IEL. Practically all i-IEL were CD3+ cells (83%). In addition, most of the i-IEL expressed Ly-2 (65%). Among the i-IEL, the level of gamma delta TCR+ cells was significantly higher (29%) than that found in spleen (3%) and PP (3%). The expression was high on CD3+ and Ly-2+ (26 and 21%, respectively) and low on L3T4+ i-IEL (< 1%). During T. spiralis infection alpha beta TCR+ CD3+, gamma delta TCR+ CD3+ and gamma delta TCR+ Ly-2+ i-IEL increased on day 4 and 7. However, infected mice displayed a reduction in i-IEL number from 14 to 29 p.i. day. At the same time the proportion of gamma delta TCR on spleen Ly-2+ and on PP CD3+ and Ly-2+ cells increased on 14 and 21 p.i. day. Adult worms were expelled from the gut by day 14. Thus, the kinetics of gamma delta TCR+ i-IEL, but not spleen and PP gamma delta TCR, corresponded to the kinetics of worm expulsion in C57BL mice. Most murine i-IEL of the gamma delta T cell lineage tend to be cytolytic when activated. We speculated that gamma delta T cells of i-IEL during the early stages of infection recognize and eliminate damaged epithelial cells generated by parasite antigens, simultaneously accelerating the worm expulsion.
A stage-by-stage study of disturbances in enterocyte proliferation in the ileum and descending colon in the course of tumour induction by treatment with 1,2-dimethylhydrazine was performed. Even at early stages, an expansion of the zone of epithelial cell proliferation in the crypts and migration of dividing cells as far as to the crypt mouth, which is a manifestation of enterocyte differentiation disturbances, were observed. Enterocytes of the crypts chiefly proliferated through a short cycle, the mean duration of which was slightly greater than in normal intestinal tissue. The reduced cell loss in the epithelium and resultant disturbances of its steady state led to the accumulation of great numbers of atypical cells in the superficial layers of the crypts and formation of carcinomas in situ in the descending colon. The microscopically unaltered sections of the mucosa, prior to development of overt neoplastic changes carcinomas in situ, superficial cancers and small-size adenocarcinomas revealed a simplified structure of enterocyte population, as compared with normal epithelium. As tumours progressed, the heterogeneity of its component cell subpopulations increased, and several subpopulations, differing in mean duration of the mitotic cycle, were formed. Pathologic mitoses made up a greater portion (50-60 per cent) of the dividing cells of the descending colon, as compared with ordinary 4 per cent at all stages of experimental tumour induction.
After the ingestion of iso-osmolar polyethylene glycol solution, the small bowel can be visualized on ultrasonography. The aim of this study was to assess sensitivity and specificity of SICUS in diagnosis of small bowel lesions. A total of 53 consecutive patients with suspected intestinal pathology underwent a diagnostic workup, including a small bowel follow-through and SICUS performed by independent operators. The sonologist was unaware of the clinical data. Diagnostic sensitivity and specificity were assessed using radiologic findings. Diagnostic sensitivity of SICUS was 100%, with a specificity of 97%. The concordance index was 0.956 (p < 0.003, kappa statistics) and the conformity between SICUS and radiology was 1. The diagnostic accuracy of SICUS to detect small bowel lesions is comparable to that of small bowel follow-through. Results of this study support the use of noninvasive, widely available, inexpensive, and nondemanding SICUS as an initial investigation in patients with suspected small bowel disease.
The objective of this study was to investigate the absorption mechanism of celiprolol as a potential source of the drug's non-linear oral pharmacokinetics by determining its intestinal permeability as a function of concentration in vivo in dogs. Solutions of different celiprolol concentrations containing propranolol as an internal absorption marker were perfused through an isolated jejunal segment and samples were analyzed by an enantioselective HPLC method (Hartmann et al., J. Chromatogr., 496 (1989) 387-396). Permeability (P(eff) x 10(4) cm/s) of celiprolol increased significantly from 1.9-2.1 for the lower concentrations to 3.2 for the highest concentration, while the variability decreased. No statistical differences in the uptake between the two enantiomers were observed. Permeability of propranolol also increased significantly with increasing celiprolol concentrations, suggesting that propranolol might be utilizing the same carrier protein. In conclusion, the non-linear and variable oral pharmacokinetics of celiprolol might be due to a non-linear saturable, possibly secretion component in its uptake mechanism.
S. typhimurium infection is associated with neutrophil infiltration within the intestinal mucosa. Neutrophil activation provides a major source of reactive oxygen species (ROS). The mucosal pathology of S. typhimurium infection may be in part due to the excessive production of these reactive species. This study was carried out to investigate if ROS play a role in mediating the changes in the structural components and functional properties of brush border membrane (BBM) in rats during S. typhimurium infection. This was done by determining the changes in the BBM extent of lipid peroxidation and absorptive function. A significant increase in the extent of lipid peroxidation of BBM during S. typhimurium infection was observed as judged by malondialdehyde (MDA) and conjugated diene formation and depletion of alpha-tocopherol and protein associated thiol groups. A significant decrease in the BBMV (brush border membrane vesicle) transport of amino acids was also observed. However there was no change in the transport of D-glucose. The decrease in amino acid transport further led to a significant decrease in the enterocyte level of protein synthesis. Exposure of BBMV to a free radical donor, cumene hydroperoxide, also led to an increase in the extent of lipid peroxidation and a decrease in the amino acid transport. Possibly ROS might play a significant role in mediating the mucosal damage during S. typhimurium infection.