ABSTRACT
BACKGROUND AND PURPOSE: The bioactive monoamine 5-HT, implicated in the pathogenesis of functional gastrointestinal disorders, is abundantly synthesized and stored in rat proximal colonic mucosa and released to the gut lumen and subepithelial space. Despite much data regarding its expression and function, the effects of luminal 5-HT on colonic anion secretion have not been fully investigated. EXPERIMENTAL APPROACH: We measured short-circuit current (Isc ) as an indicator of ion transport in mucosa-submucosa or mucosa-only preparations of rat proximal colon. Total CO2 output was measured in vitro and in vivo. Immunohistochemistry was performed to investigate the localization of 5-HT4 , NOS1 and NOS2. KEY RESULTS: Luminal 5-HT gradually increased the amplitude and sustained the elevation of Isc . Luminal 5-HT-evoked ΔIsc was acetazolamide sensitive and HCO3 (-) dependent, consistent with cytosolic carbonic anhydrase-dependent electrogenic HCO3 (-) secretion, while not affected by tetrodotoxin (TTX), atropine or indomethacin. Pretreatment with the selective 5-HT4 antagonist GR113808, but not antagonists for 5-HT3 , 5-HT6 or 5-HT7 , inhibited luminal 5-HT-evoked ΔIsc . Furthermore, luminal cisapride and tegaserod increased Isc to the same extent as did 5-HT in the presence of indomethacin and TTX. Removal of the submucosa or pretreatment with NOS inhibitors enhanced luminal 5-HT-evoked ΔIsc , suggesting that NO synthesized in the submucosa suppresses mucosal anion secretion. NOS1 and NOS2 were immunostained in the submucosal neurons and glial cells respectively. Luminal 5-HT-evoked HCO3 (-) secretion was confirmed in vivo, inhibited by co-perfusion of GR113808, but not by ondansetron. CONCLUSIONS AND IMPLICATIONS: A novel apical 5-HT4 -mediated HCO3 (-) secretory pathway and an NO-dependent inhibitory mechanism are present in the proximal colon. Luminal 5-HT-evoked HCO3 (-) secretion may be important for the maintenance of mucosal integrity by regulating luminal pH.
Subject(s)
Bicarbonates/metabolism , Colon/metabolism , Receptors, Serotonin, 5-HT4/metabolism , Serotonin/metabolism , Animals , Intestinal Mucosa/metabolism , Male , Nitric Oxide/metabolism , Rats, Sprague-Dawley , Serotonin Antagonists/pharmacologyABSTRACT
Numerous reports have shown that a diet containing large amounts of trans fatty acids (TFAs) is a major risk factor for metabolic disorders. Although recent studies have shown that TFAs promote intestinal inflammation, the underlying mechanisms are unknown. In this study, we examined the effects of dietary fat containing TFAs on dextran sodium sulphate (DSS)-induced colitis. C57 BL/6 mice were fed a diet containing 1·3% TFAs (mainly C16:1, C18:1, C18:2, C20:1, C20:2 and C22:1), and then colitis was induced with 1·5% DSS. Colonic damage was assessed, and the mRNA levels of proinflammatory cytokines and major regulators of T cell differentiation were measured. The TFA diet reduced survival and exacerbated histological damage in mice administered DSS compared with those fed a TFA-free diet. The TFA diet significantly elevated interleukin (IL)-6, IL-12p40, IL-23p19 and retinoic acid-related orphan receptor (ROR)γt mRNA levels in the colons of DSS-treated animals. Moreover, IL-17A mRNA levels were elevated significantly by the TFA diet, with or without DSS treatment. We also examined the expression of proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and peritoneal macrophages. These cells were exposed to TFAs (linoelaidic acid or elaidic acid) with or without LPS and the mRNA levels of various cytokines were measured. IL-23p19 mRNA levels were increased significantly by TFAs in the absence of LPS. Cytokine expression was also higher in LPS-stimulated cells exposed to TFAs than in unexposed LPS-stimulated cells. Collectively, our results suggest that TFAs exacerbate colonic inflammation by promoting Th17 polarization and by up-regulating the expression of proinflammatory cytokines in the inflamed colonic mucosa.
Subject(s)
Colitis/immunology , Cytokines/biosynthesis , Dextran Sulfate , Th17 Cells/metabolism , Trans Fatty Acids , Animals , Cell Differentiation/immunology , Cell Line , Colitis/chemically induced , Cytokines/genetics , Female , Inflammation/chemically induced , Inflammation/immunology , Interleukin-12 Subunit p40/biosynthesis , Interleukin-12 Subunit p40/genetics , Interleukin-17/biosynthesis , Interleukin-17/genetics , Interleukin-23 Subunit p19/biosynthesis , Interleukin-23 Subunit p19/genetics , Interleukin-6/biosynthesis , Interleukin-6/genetics , Linoleic Acid , Lipopolysaccharides , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Nuclear Receptor Subfamily 1, Group F, Member 3/biosynthesis , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Oleic Acid , Oleic Acids , RNA, Messenger/biosynthesis , Th17 Cells/immunology , Up-RegulationABSTRACT
Rubella virus (RV) infection has sporadically been linked to Guillain-Barré syndrome (GBS), but the association with RV has been based only on clinical and/or serological backgrounds. In the present case it was possible to isolate RV (genotype 1a) from cerebrospinal fluid and peripheral blood mononuclear cells of an 18-year-old woman diagnosed with GBS after clinical manifestations of rubella. This report contributes to confirm RV as one of the triggering pathogens of this peripheral nervous system disease.
Subject(s)
Guillain-Barre Syndrome/virology , Rubella virus/classification , Rubella virus/genetics , Adolescent , Blood/virology , Cerebrospinal Fluid/virology , Female , Humans , Leukocytes, Mononuclear/virology , Rubella virus/isolation & purificationABSTRACT
A new pulse wave velocity (PWV) measurement system has been developed using a novel multi-element tonometry carotid sensor combined with a heart sound sensor. In this system, PWV is derived from the time lag between the second heart sound (S2) obtained from the heart sound sensor and the dicrotic notch in the carotid pulse waveform, and the physical distance between the heart and the neck. We assessed the accuracy of the system in an animal model. The study was divided into two groups: in Group I the tonometric sensor was directly applied to the exposed artery, while in Group II the sensor was applied over the skin and subcutaneous tissues covering the artery. To examine the fidelity of the dicrotic notch, the ejection time with the tonometry sensor was compared with that obtained from the intra-arterial catheter measurement. The correlation coefficients between them were 0.99 in both groups. The bias error (defined as the mean of the differences between the tonometry and the catheter measurements) +/-2SD was 0.13+/-1.45 ms in Group I and 0.16+/-1.64 ms in Group II. These results confirmed that the arterial wall, subcutaneous tissue and skin did not affect the accuracy of the dicrotic notch fidelity. The reproducibility of the system was assessed in 18 human subjects. The 2SD of intraobserver and interobserver reproducibility of the S2-carotid PWV measurement were 0.54 and 0.38 m/s, respectively, demonstrating high reproducibility of the measurement. From a clinical point of view, the S2-carotid PWV was compared with the aortic PWV. The bias error +/-2SD between the two measurements was -0.14+/-3.24 m/s with the correlation coefficient being 0.73. Although the S2-carotid PWV may not replace the aortic PWV directly, we believe that the S2-carotid PWV with the new system may become a new clinical parameter for early detection of cardiovascular disorders such as cerebrovascular diseases.