W1351 Diversion Colitis: Beneficial Effect of Butyrate and Glutamine Enemas in an Experimental Model

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W1351 Diversion Colitis: Beneficial Effect of Butyrate and Glutamine Enemas in an Experimental Model
  intraperitonealy, was used as antagonist of PPAR- γ . Additionally, group of animals whichreceived Rosiglitazone along with BADGE, was also created. During research, animals wereunder control regarding change of body weight, presence of diarrhea and intestinal adhesionsas well as relation between bowel weight and length. Histopathological changes in largeintestine were also evaluated. Level of cytokines such as Il-1 β , Il-6, Il-10, TNF α  and MPOinserumandintestinalhomogenatewasdetermined.Results:AnimalswhichreceivedBADGEalong with DSS more significantly lost weight, more often had diarrhea and relation of bowelweight/length was higher than in the DSS group. Histopathological examination showedpresence of ulceration exceeding muscle membrane, higher expression of intestinal cryptatrophy andoedema. Administration of Rosiglitazonetogether with BADGE didnot influencereduction of inflammation. Administration of BADGE in the group of animals which receivedDSS resulted in higher concentration of TNF α  in intestinal tissue homogenate and lowerconcentration of Il-10 when comparing to DSS group. Conclusions: Inhibition of activityof PPAR- γ  receptor caused by BADGE results in higher expression of inflammatory cytokinessuch as TNF α  and in reduction of gene expression for Il-10. Consequently, it leads to slightintensification of large intestine inflammation. W1350Urocortin I Prevents Indomethacin-Induced Small Intestinal Injury ThroughActivation of Peripheral CRF2 Receptors and Adrenal Glucocorticoids Naoko Abe, Aiko Kumano, Masashi Yasuda, Koji TakeuchiBackground/Aim: Corticotropin-releasing factor (CRF), a hypothalamic neuropeptide, is theprincipal regulator of the hypothalamus-pituitary-adrenal (HPA) axis. We recently reportedthat urocortin I exhibited a protective action against indomethacin-induced small intestinallesions mediated by CRF2 receptors. However, it remains unknown whether this action of urocortin I (Ucn 1: CRF1R/CRF2R agonist:) is mediated by endogenous glucocorticoidsderived from adrenal glands. In the present study, we examined the influence of adrenalec-tomy and mifepristone (glucocorticoid antagonist) on the protective action of Ucn 1 againstNSAID-induced small intestinal damage in rats, in attempts to investigate the possibleinvolvement of adrenal glucocorticoid in this action. Methods: Male SD rats without fastingwere given indomethacin (10 mg/kg) SC and killed 24 h later to examine hemorrhagiclesions developed in the small intestine. Ucn 1 (20 µg/kg) was given IV 10 min before theadministration of indomethacin. Astressin 2B (CRF2R antagonist: 60 µg/kg) was given IV10 min before Ucn I. Mifepristone (10 mg/kg) was given PO twice 0.5 h before and 6 hafter indomethacin. Adrenalectomy was performed a week before the experiment. Intestinalmotility was measured by a balloon method, while mucus secretion was examined by PASstaining. Expressions of iNOS mRNA and CRFR protein were examined by RT-PCR and Western blotting, respectively. Results: Indomethacin caused multiple hemorrhagic lesionsin the small intestine, accompanied by a decrease in mucus secretion and increases inintestinal motility, enterobacterial invasion and iNOS expression. Urocortin I preventedthese intestinal lesions, together with suppression of such functional alterations, and theseeffectswere attenuatedby astressin-2B.Bycontrast, theseverityof theselesions wasmarkedlyaggravated by mifepristone and adrenalectomy, accompanied by further enhancement of intestinalmotility,bacterialinvasionaswellasiNOSexpression.UrocortinIpartiallyrevertedthe aggravation by adrenalectomy or mifepristone of these lesions, together with suppressionof hypermotility response and iNOS expression, but the degree of protection was much lesscompared to that observed in control rats. The expressions of CRF1R and CRF2R wereobserved in the small intestine. Conclusion: These results suggest that 1) peripheral injectionof urocortin I prevented indomethacin-induced small intestinal lesions, 2) this effect ismediated by peripheral CRF2R and partly mediated by glucocorticoids, and 3) the HPAaxis plays a role in protecting the small intestine against NSAID-induced damage viaadrenal glucocorticoids. W1351Diversion Colitis: Beneficial Effect of Butyrate and Glutamine Enemas in anExperimental Model Rodrigo G. Pacheco, Christiano C. Esposito, Alberto Schanaider, Leonardo P. Quintella, Vera L. Chagas, Cesonia A. Martinusso, Alyson do Rosario, Morgana T. Castelo-Branco,Heitor SouzaBackground & aims: Diversion colitis is a complex inflammatory disease involving the closedsegment of the colon, after colostomy. Clinical manifestations include abdominal pain,abundant mucus discharge, and bleeding. Endoscopic and histologic findings are non-specific and the disease pathogenesis remains unclear. However, recently, some new datasuggest the possibility that the lack of luminal nutrients may be of crucial role in thedevelopmentofthedisease.Wehypothesizedthattheadministrationofbutyrateorglutamine,essential colonocyte nutrients, could alleviate inflammation and help in tissue repair in amodel of diversion colitis. Methods: Male Wistar rats with an average weight of 250g, wereanesthetized and submitted to a surgical procedure consisting of a midline incision, followedby a left colostomy, with the closure of the distal colon segment. Animals were then dividedinto 4 groups in order to receive different treatments: a) no treatment; b) saline enemas; c)glutamine enemas; d) butyrate enemas. Enemas were administered intra-rectally in a weeklybasis in the closed segment of the colon. Colonoscopy was performed every 4 weeks, beingthe total follow-up of 12 weeks. The different treatments were evaluated using scores of video-endoscopic recordings, andhistologic scores by twoindependent pathologists. Results:The inflammatory process of diversion colitis was well characterized in the experimentalmodel. Colonoscopy of the diverted segment showed a fragile mucosa, with hyperemia,increasednumberof vessels,spontaneousbleeding,andincreased mucoussecretion.Animalstreated with either glutamine or butyrate showed a significant reduction in both the colonos-copic (p<0.02), and the histologic (p<0.01) scores. Conclusion: This experimental modelof diversion colitis was shown to be effective and reproducible. Treatment with glutamineor butyrate enemas effectively attenuates the inflammation in the current model. Theseresultsindicatethepathogenicroleofthelackofspecificluminalnutrientsintheinflammatoryprocess, and may support the use of glutamine or butyrate enemas as an effective therapeuticoption for diversion colitis. S-705  AGA Abstracts W1352Nutritional Supplementation With Transforming Growth Factor-Beta (TGF- β )Affects Enterocyte Turnover in Correlation With TGF- β  Receptor ExpressionAfter Massive Small Bowel Resection in a Rat Ron Shaoul, Jorge Mogilner, Arnold G. Coran, Elena Chemodanov, Igor SukhotnikBackground:Transforminggrowthfactorbetahasbeenshowntoaffectepithelialcelldifferen-tiation and proliferation through epithelial-mesenchymal and epithelial-immune cell interac-tion. In the present study, we evaluated the effect of TGF- β 2-enriched polymeric diet(Modulen IBD) on enterocyte turnover and correlated it with TGF- β  receptor (TGF- β r)expression alongthe villus-crypt axisin arat model ofshort bowel syndrome(SBS). Methods:Male rats were divided into four groups: Sham rats underwent bowel transection, Sham-TGF- β  rats underwent bowel transection and were treated with diet enriched with TGF- β (Modulen IBD) from the 4th postoperative day, SBS rats underwent a 75% bowel resection,and SBS- TGF- β  rats underwent bowel resection and were treated with Modulen similarlyto group B. Parameters of intestinal adaptation, enterocyte proliferation and apoptosis weredeterminedonday15.Real-timePCRwasusedtodeterminebaxandbcl-2mRNAexpression.TGF- β r expression in villus tips, lateral villi and crypts was assessed by immunohistochem-istry. The effect of TGF- β  on enterocyte turnover for each compartment was evaluated incorrelation with TGF- β r expression. Results: Exposure to dietary TGF- β  led to increasedTGF- β r expression in both sham and SBS animals. TGF- β r expression in crypts increasedin SBS-TGF- β  rats (vs SBS rats) and was accompanied by a mild decrease in enterocyteproliferation and concomitant increase in cell apoptosis. A significant increase in TGF- β rexpression at the tip of the villous in SBS-TGF- β  rats was accompanied by a decreased cellapoptosis in this compartment. Decreased bax and increased bcl-2 mRNA expression wasresponsible for decrease in apoptosis in SBS-TGF- β  group. Conclusions: In a rat model of SBS, dietary TGF- β  decreased enterocyte proliferation and increased cell apoptosis in crypts,but decreased cell apoptosis in villi. The inhibiting effect of TGF- β  on enterocyte turnovercorrelates with TGF- β  receptor expression along the villus-crypt axis. W1353Pharmacological Modulation of Intestinal Inflammation by DexamethasoneReversed the Gastrointestinal Dysmotility Associated With 5-Fluorouracil (5-FU)- Induced Intestinal Mucositis in Rats Larisse T. Lucetti, Graciela J. Oliveira, Jand Venes R. Medeiros, André Luiz R. Barbosa,Gerly Anne C. Brito, Ronaldo A. Ribeiro, Pedro Marcos G. Soares, Marcellus H. SouzaBackground & Aims: Recently, we demonstrated that during 5-FU-induced intestinal mucos-itis, there was a delay in gastric emptying and a significant increase in gastric fundus andduodenum smooth muscle contraction (Soares PM et al., Cancer Chemother Pharmacol.2008 Dec;63:91-8). Our hypothesis was that the pharmacological modulation of intestinalinflammation could reverse the gastrointestinal dysmotility associated with 5-FU- inducedintestinal inflammatory damage. Methods: Wistar rats received 5-FU (150 mg/Kg, i.p.) orsaline. Other group was treated with 5-FU + dexamethasone (2.5 mg/Kg, s.c., per day). After 3rd day, sections of duodenum were removed for assessment of epithelial damage,myeloperoxidase (MPO) activity and cytokines (TNF- α , IL-1 β ) concentrations by ELISA. Inorder to study gastrointestinal motility, on the 3rd day after saline, 5-FU or 5-FU + dexame-thasone treatment, rats were gavage-fed (1.5 mL) with the test meal (5% glucose solutionwith 0.05 g/mL) phenol red) and killed 20 min later. Gastric emptying was measured byspectrophotometry. Statistical analysis was performed with ANOVA and Bonferroni test.Results: 5-FU induced a significant (p<0.05) epithelial intestinal damage (reduction of villusheight/crypts depht reason) in duodenum (saline= 3.38±0.11, 5- FU= 0.67±0.06), increasedof histologic scores [saline= 0 (0-0), 5-FU= 2 (2-3)], MPO activity (number neutrophil/mgof tissue)(saline= 0.90±0.57, 5-FU= 69.10±5.67)and cytokines concentration(pg/ml) (TNF- α - saline= 153.70±80.90, 5-FU= 585.10±99.27; IL-1 β - saline= 361.90±46.11, 5-FU=1494.00±163.60). In the gastrointetinal motility, we observed an increase in gastric retentionafter5-FUtreatment(saline=43.48±2.64%,5-FU=63.21±1.79%).Dexamethasonedecreased(p<0.05) the 5-FU- induced intestinal injury [morphometric; 5-FU + dexamethasone =1.79±0.12 and histologic scores; 0 (0-1)], reduced MPO activity (45.70±7.14) and cytokinesconcentration (TNF- α = 167.40 ± 28.32; IL-1 β = 1030.00±101.90). In the gastrointetinalmotility, dexamethasone also decreased the gastric retention induced by 5-FU (5-FU +dexamethasone = 53.82±1.26%).Conclusion: Dexamethasone reversed the 5-fluorouracil (5-FU)- induced inflammatory intestinal damage and gastrointestinal dysmotility in rats Finan-cial support: CNPq- Brazil. W1354Cinacalcet, an Extracellular Calcium-Sensing Receptor Agonist, ProtectsAgainst NSAID-Induced Damage in Rat Small Intestines Naoto Kurata, Shusaku Hayashi, Aya Yamaguchi, Koji TakeuchiBackground/Aim: The extracellular calcium-sensing receptor (CaSR), a G protein- coupledcell surface receptor, is expressed in diverse tissues in mammalian and plays a role in theregulation of calcium homeostasis and salt/water balance. An increasing number of studieshave recently demonstrated a regulator role for CaSR in various functions of the gastrointesti-nal tract, such as gastric acid secretion and colonic fluid transport. However, it remainsunknown whether CaSR has any effect on the intestinal ulcerogenic response caused bynonsteroidal anti-inflammatory drugs (NSAIDs). In the present study, we examined theeffect of cinacalcet, a CaSR agonist, on the small intestinal lesions induced by loxoprofenNa, one of NSAIDs frequently used in Asian countries, and investigated the mechanismsinvolved in the protective action. Methods: Male SD rats were used without fasting. Theanimals were administered loxoprofen (60 mg/kg, p.o.) and killed 24 h later to examinethe lesions developed in the small intestine. Cinacalcet (1-100 mg/kg) was given p.o. 30minbeforeadministrationofloxoprofen.Enterobacterialcountinthemucosawasdeterminedby a culture method 6 h later, while the protein expression of inducible nitric oxidesynthase (iNOS) in the mucosa was examined by western blotting. Results: Loxoprofencausedhemorrhagiclesionsinthesmallintestine,accompaniedbyincreasesinenterobacterial       A      G      A      A      b    s     t    r    a    c     t    s
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