Disodium Cromoglycate Reverses Colonic Visceral Hypersensitivity and Influences Colonic Ion Transport in a Stress-Sensitive Rat Strain

The interface between psychiatry and stress-related gastrointestinal disorders (GI), such as irritable bowel syndrome (IBS), is well established, with anxiety and depression the most frequently occurring comorbid conditions. Moreover, stress-sensitive Wistar Kyoto (WKY) rats, which display anxiety- and depressive-like behaviors, exhibit GI disturbances akin to those observed in stress-related GI disorders. Additionally, there is mounting preclinical and clinical evidence implicating mast cells as significant contributors to the development of abdominal visceral pain in IBS. In this study we examined the effects of the rat connective tissue mast cell (CTMC) stabiliser, disodium cromoglycate (DSCG) on visceral hypersensitivity and colonic ion transport, and examined both colonic and peritoneal mast cells from stress-sensitive WKY rats. DSCG significantly decreased abdominal pain behaviors induced by colorectal distension in WKY animals independent of a reduction in colonic rat mast cell mediator release. We further demonstrated that mast cell-stimulated colonic ion transport was sensitive to inhibition by the mast cell stabiliser DSCG, an effect only observed in stress-sensitive rats. Moreover, CTMC-like mast cells were significantly increased in the colonic submucosa of WKY animals, and we observed a significant increase in the proportion of intermediate, or immature, peritoneal mast cells relative to control animals. Collectively our data further support a role for mast cells in the pathogenesis of stress-related GI disorders.     

Reduction of colonic mucus by repeated short-term stress enhances experimental colitis in rats.

The role of stress in inflammatory bowel disease remains debated and few studies have tested the role of stress in conjunction with experimental animal models of colitis. In this investigation we tested the hypothesis that cold-restraint stress would adversely effect the severity of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats, and examined mechanisms for the response. Results indicated that increasing intermittent prior exposures to stress significantly enhanced TNBS-induced colitis severity. An associated stress-induced decrease in colonic mucin glycoprotein content, reduction in goblet cells, and histochemical mucin suggested reduced mucin was a pathogenetic factor. Myeloperoxidase content increased and mast cell counts in the colon decreased but colonic permeability only temporarily increased with increasing stress exposure. Prior adrenalectomy or administration of an adrenergic blocking agent did not prevent the colonic changes to stress, but mast cell stabilization or inhibition of cholinergic pathways reduced the stress-induced colonic changes.     

Changes in number of serotonin-containing cells and serotonin levels in the intestinal mucosa of rats with colitis induced by dextran sodium sulfate

The role of serotonin in the pathogenesis of inflammatory bowel disease has not been fully studied. We examined the changes in the serotonin level and the density of serotonin-containing enterochromaffin (EC) and mast cells in the intestinal mucosa of dextran sodium sulfate (DSS)-induced colitis in rats. Rats were treated with 1.5% DSS for 1 month. Serotonin levels were biochemically measured and the density of epithelial EC cells and mucosal mast cells was quantified by serotonin immunohistochemistry. DSS caused malnutrition due to chronic diarrhea. Infiltrated inflammatory cells were microscopically observed in the colonic wall with intact epithelium. The serotonin content in the mucosa/submucosa tissue was increased in the proximal and distal colon in DSS-treated rats, compared to that in control rats. The density of EC cells in the epithelium also increased in the proximal and distal colon in DSS-treated rats. In contrast, the density of mast cells in the lamina propria dramatically increased in the distal, but not in the proximal colon in DSS-treated rats. This discrepancy implies the serotonin released from EC cells and from mast cells may play different roles in the pathogenesis of DSS-induced colitis. Accepted: 30 July 1999     

Chronic peripheral administration of corticotropin-releasing factor causes colonic barrier dysfunction similar to psychological stress

Chronic psychological stress causes intestinal barrier dysfunction and impairs host defense mechanisms mediated by corticotrophin-releasing factor (CRF) and mast cells; however, the exact pathways involved are unclear. Here we investigated the effect of chronic CRF administration on colonic permeability and ion transport functions in rats and the role of mast cells in maintaining the abnormalities. CRF was delivered over 12 days via osmotic minipumps implanted subcutaneously in wild-type (+/+) and mast cell-deficient (Ws/Ws) rats. Colonic segments were excised for ex vivo functional studies in Ussing chambers [short-circuit current (Isc), conductance (G), and macromolecular permeability (horseradish peroxidase flux)], and analysis of morphological changes (mast cell numbers and bacterial host-interactions) was determined by light and electron microscopy. Chronic CRF treatment resulted in colonic mucosal dysfunction with increased Isc, G, and horseradish peroxidase flux in+/+but not in Ws/Ws rats. Furthermore, CRF administration caused mast cell hyperplasia and abnormal bacterial attachment and/or penetration into the mucosa only in+/+rats. Finally, selective CRF agonist/antagonist studies revealed that stimulation of CRF-R1 and CRF-R2 receptors induced the elevated secretory state and permeability dysfunction, respectively. Chronic CRF causes colonic barrier dysfunction in rats, which is mediated, at least in part, via mast cells. This information may be useful in designing novel treatment strategies for stress-related gastrointestinal disorders.     

Critical role for mast cells in the pathogenesis of 2,4-dinitrobenzene-induced murine colonic hypersensitivity reaction

The immunological mechanisms underlying the role of mast cells in the pathogenesis of inflammatory bowel disease (IBD) are poorly defined. In this study, non-IgE mediated colonic hypersensitivity responses in BALB/c mice induced by skin sensitization with dinitrofluorobenzene (DNFB) followed by an intrarectal challenge with dinitrobenzene sulfonic acid featured as a model to study the role of mast cells in the development of IBD. Vehicle- or DNFB-sensitized mice were monitored for clinical symptoms and inflammation 72 h after dinitrobenzene sulfonic acid challenge. DNFB-sensitized mice developed diarrheic stool, increased colonic vascular permeability, hypertrophy of colonic lymphoid follicles (colonic patches), and showed cellular infiltration at the microscopic level. Increased numbers of mast cells were found in the colon of DNFB-sensitized mice located in and around colonic patches associated with elevated levels of mouse mast cell protease-1 in plasma indicating mast cell activation. Colonic patches of DNFB mice, stimulated in vitro with stem cell factor indicated that an increase in TNF-alpha levels in the colon is mainly mast cell originated. Finally, neutrophil infiltration was observed in the colon of DNFB-sensitized mice. Induction of this model in mast cell-deficient WBB6F(1) W/W(v) mice shows a profound reduction of characteristics of the colonic hypersensitivity reaction. Reconstitution with bone marrow-derived mast cells in WBB6F(1) W/W(v) mice fully restored the inflammatory response. This study demonstrates the importance of mast cells in the development of clinical symptoms and inflammation in the presented murine model for IBD.     

Implication of TNF-alpha convertase (TACE/ADAM17) in inducible nitric oxide synthase expression and inflammation in an experimental model of colitis

Tumour necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine which is shed in its soluble form by a disintegrin and metalloproteinase (ADAM) called TNF-alpha convertase (TACE; ADAM17). TNF-alpha plays a role in inflammatory bowel disease (IBD) and is involved in the expression of inducible nitric oxide synthase (iNOS) which has also been implicated in IBD. The study was designed to investigate whether colitis induced by trinitrobenzene sulphonic acid (TNBS) in rats produces an increase in TACE activity and/or expression and whether its pharmacological inhibition reduces TNF-alpha levels, iNOS expression and colonic damage in this model. TNBS (30 mg in 0.4 ml of 50% ethanol) was instilled into the colon of female Wistar rats. Saline or TACE inhibitor BB1101 (10 mg/kg/day) was administered intraperitoneally 5 days after TNBS instillation. On day 10, colons were removed and assessed for pathological score, myeloperoxidase (MPO), NO synthase (NOS), TACE enzymatic activity and protein levels, colonic TNF-alpha and NOx- levels. Instillation of TNBS caused an increase in TACE activity and expression and the release of TNF-alpha. TNBS also resulted in iNOS expression and colonic damage. BB1101 blocked TNBS-induced increase in TACE activity, TNF-alpha release and iNOS expression. Concomitantly, BB1101 ameliorated TNBS-induced colonic damage and inflammation. TNBS causes TNF-alpha release by an increase in TACE activity and expression and this results in the expression of iNOS and subsequent inflammation, suggesting that TACE inhibition may prove useful as a therapeutic means in IBD.     

Increased Expression of Colonic Mucosal Melatonin in Patients with Irritable Bowel Syndrome Correlated with Gut Dysbiosis

Dysregulation of the gut microbiota/gut hormone axis contributes to the pathogenesis of irritable bowel syndrome (IBS). Melatonin plays a beneficial role in gut motility and immunity. However, altered expression of local mucosal melatonin in IBS and its relationship with the gut microbiota remain unclear. Therefore, we aimed to detect the colonic melatonin levels and microbiota profiles in patients with diarrhea-predominant IBS (IBS-D) and explore their relationship in germ-free (GF) rats and BON-1 cells. Thirty-two IBS-D patients and twenty-eight healthy controls (HCs) were recruited. Fecal specimens from IBS-D patients and HCs were separately transplanted into GF rats by gavage. The levels of colon mucosal melatonin were assessed by immunohistochemical methods, and fecal microbiota communities were analyzed using 16S rDNA sequencing. The effect of butyrate on melatonin synthesis in BON-1 cells was evaluated by ELISA. Melatonin levels were significantly increased and negatively correlated with visceral hypersensitivity in IBS-D patients. GF rats inoculated with fecal microbiota from IBS-D patients had high colonic melatonin levels. Butyrate-producing Clostridium cluster XIVa species, such as Roseburia species and Lachnospira species, were positively related to colonic mucosal melatonin expression. Butyrate significantly increased melatonin secretion in BON-1 cells. Increased melatonin expression may be an adaptive protective mechanism in the development of IBS-D. Moreover, some Clostridium cluster XIVa species could increase melatonin expression via butyrate production. Modulation of the gut hormone/gut microbiota axis offers a promising target of interest for IBS in the future.     

Schisandra chinensis reverses visceral hypersensitivity in a neonatal-maternal separated rat model

Visceral hypersensitivity is an important characteristic feature of functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). This study evaluated the effect of Schisandra chinensis on visceral hyperalgesia induced by neonatal maternal separation (NMS) in an IBS rat model. The visceromotor responses to colorectal balloon distension (CRD) were measured by abdominal withdrawal reflex (AWR) and electromyographic (EMG) activities. NMS control rats (receiving vehicle) underwent aggravated visceral pain in response to CRD as compared to normal rats, evidenced by the reduced pain threshold, enhanced AWR scores and EMG responses. Treatment with a 70% ethanol extract of S. chinensis (0.3g/kg and 1.5g/kg/day) for 7 days resulted in an increase in the pain threshold (NMS control: 19.1±1.0mmHg vs low-dose: 24.8±1.3mmHg and high-dose: 25.2±1.8mmHg, p<0.01), and abolished the elevated AWR and EMG responses to CRD in NMS rats (AUC values of EMG response curve were: 1952±202 in NMS control group vs 1074±90 in low-dose group and 1145±92 in high-dose group, p<0.001), indicating that S. chinensis could reverse the visceral hypersensitivity induced by early-life stress event. The result of ELSA measurement shows that the elevated serotonin (5-HT) level in the distal colon of NMS rats returned to normal level after treatment with S. chinensis. Moreover, the increase in pain threshold in rats treated with S. chinensis was associated with a decline of the mRNA level of 5-HT(3) receptor in the distal colon. All available results demonstrate that S. chinensis can reverse visceral hypersensitivity induced by neonatal-maternal separation, and the effect may be mediated through colonic 5-HT pathway in the rat.     

IMPLICATION OF TNF-α CONVERTASE (TACE/ADAM17) IN INDUCIBLE NITRIC OXIDE SYNTHASE EXPRESSION AND INFLAMMATION IN AN EXPERIMENTAL MODEL OF COLITIS

Tumour necrosis factor-α (TNF-α) is a pro-inflammatory cytokine which is shed in its soluble form by a disintegrin and metalloproteinase (ADAM) called TNF-α convertase (TACE; ADAM17). TNF-α plays a role in inflammatory bowel disease (IBD) and is involved in the expression of inducible nitric oxide synthase (iNOS) which has also been implicated in IBD. The study was designed to investigate whether colitis induced by trinitrobenzene sulphonic acid (TNBS) in rats produces an increase in TACE activity and/or expression and whether its pharmacological inhibition reduces TNF-α levels, iNOS expression and colonic damage in this model. TNBS (30 mg in 0.4 ml of 50% ethanol) was instilled into the colon of female Wistar rats. Saline or TACE inhibitor BB1101 (10 mg/kg/day) was administered intraperitoneally 5 days after TNBS instillation. On day 10, colons were removed and assessed for pathological score, myeloperoxidase (MPO), NO synthase (NOS), TACE enzymatic activity and protein levels, colonic TNF-α and NO−x levels. Instillation of TNBS caused an increase in TACE activity and expression and the release of TNF-α. TNBS also resulted in iNOS expression and colonic damage. BB1101 blocked TNBS-induced increase in TACE activity, TNF-α release and iNOS expression. Concomitantly, BB1101 ameliorated TNBS-induced colonic damage and inflammation. TNBS causes TNF-α release by an increase in TACE activity and expression and this results in the expression of iNOS and subsequent inflammation, suggesting that TACE inhibition may prove useful as a therapeutic means in IBD.     

Elucidation of colon-protective efficacy of diosgenin in experimental TNBS-induced colitis: inhibition of NF-κB/IkB-α and Bax/Caspase-1 signaling pathways

ABSTRACT

The aim of present investigation was to elucidate the unrevealed beneficial role of diosgenin against an experimental model of TNBS (2,4,6-trinitrobenzenesufonic acid)-induced ulcerative colitis (UC). Colitis was induced in Sprague-Dawley rats by intrarectal administration of TNBS (in 50% ethanol). Then animals were treated with diosgenin (50, 100, and 200 mg/kg) for 14 days. Various biochemical, behavioral, molecular, and histological analysis was performed. Diosgenin significantly decreased (p < 0.05) TNBS-induced elevated colonic oxido-nitrosative damage, myeloperoxidase, hydroxyproline, mRNA expressions of proinflammatory cytokines (TNF-α, IL-1β, IL-6, and IFN-γ) and inflammatory markers (iNOs and COX-2) induced by TNBS. Western blot analysis relevated that TNBS-induced up-regulated protein expressions of NF-κB, IκBα, Bax, and Caspase-1 were markedly decreased (p < 0.05) by diosgenin treatment. It also markedly ameliorated the histological insults induced in the colon by TNBS. In conclusion, diosgenin exerts its colon-protective efficacy probably through the inhibition of NF-κB/IkB-α and Bax/Caspase-1 signaling pathways to experimental TNBS-induced ulcerative colitis.     

Dietary Resistant Starch Alters the Characteristics of Colonic Mucosa and Exerts a Protective Effect on Trinitrobenzene Sulfonic Acid-induced Colitis in Rats

The protective effect of a dietary high-amylose cornstarch (HAS) against trinitrobenzene sulfonic acid (TNBS)-induced colitis was examined in rats. Rats were fed a HAS-free basal diet or, a 15% or 30% HAS supplemented diet for 10 d, and then received intracolonic TNBS to induce colitis and fed the respective diets for a further 8 d. HAS ingestion significantly protected colonic injuries as evidenced by lower colonic myeloperoxidase activity. Rats fed the HAS diet showed greater cecal short-chain fatty acid (SCFA) production than those fed the basal diet. Further, just before TNBS administration, HAS ingestion dose-dependently increased fecal and cecal mucin contents, and protein and nucleic acid contents in the colonic mucosa. HAS ingestion also reduced colonic permeability. The protective effect of HAS ingestion on TNBS-induced colitis is perhaps exerted through alterations in colonic mucosa, possibly due to cecal SCFA production.     

Dietary resistant starch alters the characteristics of colonic mucosa and exerts a protective effect on trinitrobenzene sulfonic acid-induced colitis in rats

The protective effect of a dietary high-amylose cornstarch (HAS) against trinitrobenzene sulfonic acid (TNBS)-induced colitis was examined in rats. Rats were fed a HAS-free basal diet or, a 15% or 30% HAS supplemented diet for 10 d, and then received intracolonic TNBS to induce colitis and fed the respective diets for a further 8 d. HAS ingestion significantly protected colonic injuries as evidenced by lower colonic myeloperoxidase activity. Rats fed the HAS diet showed greater cecal short-chain fatty acid (SCFA) production than those fed the basal diet. Further, just before TNBS administration, HAS ingestion dose-dependently increased fecal and cecal mucin contents, and protein and nucleic acid contents in the colonic mucosa. HAS ingestion also reduced colonic permeability. The protective effect of HAS ingestion on TNBS-induced colitis is perhaps exerted through alterations in colonic mucosa, possibly due to cecal SCFA production.     

Luminally released serotonin stimulates colonic motility and accelerates colonic transit in rats

Enterochromaffin (EC) cells of the epithelial cells release 5-HT into the lumen, as well as basolateral border. However, the physiological role of released 5-HT into the lumen is poorly understood. Concentrations of 5-HT in the colonic mucosa, colonic lumen, and feces were measured by HPLC in rats. To investigate whether intraluminal 5-HT accelerates colonic transit, 5-HT and (51)Cr were administered into the lumen of the proximal colon, and colonic transit was measured. To investigate whether 5-HT is released into the lumen, we used an ex vivo model of isolated vascularly and luminally perfused rat proximal colon. To investigate whether luminal 5-HT is involved in regulating stress-induced colonic motility, the distal colonic motility was recorded under the stress loading, and a 5-HT(3) receptor antagonist (ondansetron, 10(-6) M, 0.5 ml) was administered intraluminally of the distal colon. Tissue content of 5-HT in the proximal colon (15.2 +/- 4.3 ng/mg wet tissue) was significantly higher than that in the distal colon (3.3 +/- 0.7 ng/mg wet tissue), while fecal content and luminal concentration of 5-HT was almost the same between the proximal and distal colon. Luminal administration of 5-HT (10(-6)-10(-5) M) significantly accelerated colonic transit. Elevation of intraluminal pressure by 10 cmH(2)O significantly increased the luminal concentration of 5-HT but not the vascular concentration of 5-HT. Stress-induced stimulation of the distal colonic motility was significantly attenuated by the luminal administration of ondansetron. These results suggest that luminally released 5-HT from EC cells plays an important role in regulating colonic motility in rats.     

Effects of proanthocyanidins from grape seed on treatment of recurrent ulcerative colitis in rats

The aim of the present study was to investigate the therapeutic effect and mechanism of proanthocyanidins from grape seed (GSPE) in the treatment of recurrent ulcerative colitis (UC) in rats. To induce recurrent colitis, rats were instilled with 2,4,6-trinitrobenzenesulfonic acid (TNBS) (80?mg/kg) into the colon through the cannula in the first induced phase, and then the rats were instilled a second time with TNBS (30?mg/kg) into the colon on the sixteenth day after the first induction UC. Rats were intragastrically administered GSPE (200?mg/kg) per day for 7?days after twice-induced colitis by TNBS. Sulfasalazine at 500?mg/kg was used as a positive control drug. Rats were killed 7?days after GSPE treatment. The colonic injury and inflammation were assessed by macroscopic and macroscopic damage scores, colon weight/length ratio (mg/cm), and myeloperoxidase activity. Then, superoxide dismutase, glutathione peroxidase, inducible nitric oxide synthase (iNOS) activities, and the levels of malonyldialdehyde, glutathione, and nitric oxide in serum and colonic tissues were measured. Compared with the recurrent UC group, GSPE treatment facilitated recovery of pathologic changes in the colon after induction of recurrent colitis, as demonstrated by reduced colonic weight/length ratio and macroscopic and microscopic damage scores. The myeloperoxidase and iNOS activities with malonyldialdehyde and nitric oxide levels in serum and colon tissues of colitis rats were significantly decreased in the GSPE group compared with those in the recurrent UC group. In addition, GSPE treatment was associated with notably increased superoxide dismutase, glutathione peroxidase activities, and glutathione levels of colon tissues and serum of rats. GSPE exerted a protective effect on recurrent colitis in rats by modifying the inflammatory response, inhibiting inflammatory cell infiltration and antioxidation damage, promoting damaged tissue repair to improve colonic oxidative stress, and inhibiting colonic iNOS activity to reduce the production of nitric oxide.     

Effects of short chain fatty acids on colonic Na+ absorption and enzyme activity

Short chain fatty acids (SCFA) stimulate colonic Na+ absorption and inhibit cAMP and cGMP-mediated Cl- secretion. It is uncertain whether SCFA have equivalent effects on absorption and whether SCFA inhibition of Cl- secretion involves effects on mucosal enzymes. Unidirectional Na+ fluxes were measured across stripped colonic segments in the Ussing chamber. Enzyme activity was measured in cell fractions of scraped colonic mucosa. Mucosal 50 mM acetate, propionate, butyrate and poorly metabolized isobutyrate stimulated proximal colon Na+ absorption equally (300%). Neither 2-bromo-octanoate, an inhibitor of beta-oxidation, nor carbonic anhydrase inhibition affected this stimulation. All SCFA except acetate stimulated distal colon Na+ absorption 200%. Only one SCFA affected proximal colon cGMP phosphodiesterase (PDE) (18% inhibition by 50 mM butyrate). All SCFA at 50 mM stimulated distal colon cAMP PDE (24-43%) and decreased forskolin-stimulated mucosal cAMP content. None of the SCFA affected forskolin-stimulated adenylyl cyclase in distal colon or ST(a)-stimulated guanylyl cyclase in proximal colon. Na+-K+-ATPase in distal colon was inhibited 23-51% by the SCFA at 50 mM. We conclude that all SCFA (except acetate in distal colon) stimulate colonic Na+ absorption equally, and the mechanism does not involve mucosal SCFA metabolism or carbonic anhydrase. SCFA inhibition of cAMP-mediated secretion may involve SCFA stimulation of PDE and inhibition of Na+-K+-ATPase.     

Effects of neonatal maternal separation on neurochemical and sensory response to colonic distension in a rat model of irritable bowel syndrome

Early life stress has been implicated as a risk factor for irritable bowel syndrome (IBS). We studied the effect of neonatal maternal separation on the visceromotor response and the expression of c-fos, 5-HT, and its receptors/transporters along the brain-gut axis in an animal model of IBS. Male neonatal Sprague-Dawley rats were randomly assigned to a 3-h daily maternal separation (MS) or nonhandling (NH) on postnatal days 2-21. Colorectal balloon distention (CRD) was performed for assessment of abdominal withdrawal reflex as a surrogate marker of visceral pain. Tissues from dorsal raphe nucleus in midbrain, lumbar-sacral cord, and distal colon were harvested for semiquantitative analysis of c-fos and 5-HT. The expression of 5-HT expression, 5-HT3 receptors, and 5-HT transporter were analyzed by RT-PCR. Pain threshold was significantly lower in MS than NH rats. The abdominal withdrawal reflex score in response to CRD in MS rats was significantly higher with distension pressures of 40, 60, and 80 mmHg. In MS rats, the number of c-fos-like immunoreactive nuclei at dorsal horn of lumbar-sacral spinal cord increased significantly after CRD. 5-HT content in the spinal cord of MS rats was significant higher. In the colon, both 5-HT-positive cell number and 5-HT content were comparable between MS and NH groups before CRD. Post-CRD only MS rats had significant increase in 5-HT content. Protein and mRNA expression levels of 5-HT3 receptors and 5-HT transporter were similar in MS and NH rats. Neonatal maternal separation stress predisposes rats to exaggerated neurochemical responses and visceral hyperalgesia in colon mimicking IBS.     

Desulfonation of a colitis inducer 2,4,6-trinitrobenzene sulfonic acid produces sulfite radical

2,4,6-Trinitrobenzene sulfonic acid (TNBS) has been used in vivo to induce colitis. With the nitroreductase of intestinal cells, TNBS underwent redox cycling to produce TNBS-nitro and superoxide radical anions which are thought to be involved in initial oxidative reactions that lead to colonic injury. In this study, we demonstrated that the TNBS desulfonative reaction with tissue amino acids produces sulfite which is subsequently oxidized to sulfite radical. Sulfite radical was measured using a spin trapping methodology. Sulfite radical adducts of 5,5-dimethyl-1-pyrroline N-oxide (DMPO) or 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide (DEPMPO) were detected in a mixture of TNBS and lysine, xanthine oxidase, red blood cells, colonic mucosal or submucosal muscle tissues. TNBS alone did not produce sulfite radical, indicating that its formation required the presence of amino acids. Because sulfite radical is the precursor of highly reactive sulfiteperoxyl and sulfate radicals, our data imply that these sulfite-derived free radicals may also contribute to oxidative reactions leading to colonic injury in TNBS-induced colitis.     

Effects of histamine H1 antagonist dithiaden on acetic acid-induced colitis in rats.

To assess the possible involvement of mast cells and/or their mediators in inflammatory bowel diseases, the effect of the histamine H1 antagonist Dithiaden was studied on a model of acetic acid-induced colitis in rats. Dithiaden pretreatment by intracolonic administration was found to reduce the extent of acute inflammatory colonic injury. This was manifested by a decrease in the score of gross mucosal injury, by lowered colonic wet weight and by diminished myeloperoxidase activity reflecting reduced leukocyte infiltration. Vascular permeability and gamma-glutamyl transpeptidase activity, elevated by acetic acid exposure, were decreased after Dithiaden pretreatment. The results indicate that locally administered Dithiaden may protect the colonic mucosa against an acute inflammatory attack by interfering with the action of the major mast cell mediator histamine.