Ileitis In Rats Research Articles

Histological study of the effect of curcumin on indomethacin-induced ileitis in adult male albino rats

Background Ileitis induced by indomethacin represents a well-standardized model in the study of acute and chronic inflammation of the intestine. Curcumin is an orange-yellow component of the herb turmeric. It has potent anti-inflammatory, antioxidant, antimicrobial, and anticancer effects. Aim This work was performed to show the effect of curcumin on indomethacin-induced ileitis in rats using H&E stain. Materials and methods Thirty-six mature male albino rats (160–200 g) were used in this study. They were separated into four formain groups; control group: 8 rats, group I: 8 rats that received oral aqueous suspension of curcumin 100 mg/kg daily; group II: 10 rats included subgroups (IIA & IIB): ileitis was induced by subcutaneous injection of two doses of indomethacin; each dose was 7.5 mg/kg separated by 24 hours, the rats were then killed on the 3rd and the 18th day, respectively, and group III: 10 rats included subgroups (IIIA& IIIB): the ileitis group was treated with an oral aqueous suspension of curcumin 100 mg/kg daily and then the rats were killed on the 3rd and 18th day respectively. Results Subgroups IIA and IIB revealed sloughing of surface epithelium in the lumen of the intestine, ulceration, a significant decrease of villus height at H&E sections, and inflammatory cellular infiltration. Subgroups IIIA and IIIB showed marked improvement in the pathological changes of induced ileitis. Conclusion Curcumin could decrease ileitis induced by indomethacin in rats. So, it could be useful for the treatment of intestinal injury.

DOP68 CD-TREAT diet induces remission and improves quality of life in an open label trial in children and adults with active Crohn’s Disease

Abstract Background Exclusive enteral nutrition (EEN) is an established induction treatment for active Crohn’s disease (CD) with a proposed mechanism of action involving the gut microbiome. We have previously shown that CD-TREAT diet, a food-based diet with similar dietary profile to EEN, improves rat ileitis and replicates the effect of EEN on the gut microbiome of healthy volunteers and animal models. Here, we test the efficacy of CD-TREAT diet to induce clinical remission in active CD. Methods This is an open-label study in children (wPCDAI≥12.5) and adults (HBI≥5) with active CD. Primary outcome was clinical response (wPCDAI fall≥17.5; HBI fall≥3) or clinical remission (wPCDAI< 12.5; HBI<5) after 8 week treatment with CD-TREAT. Secondary outcomes included improvement of quality of life (QoL) and reduction in faecal calprotectin (FC) levels. Since CD-TREAT diet is gluten-free, adherence to treatment was assessed by the detection of the gluten immunogenic peptide (GIP) in faeces. Data are presented with median (IQR). Results 25 children, [age, 14.4 (12.5,15.7) years] and 32 adults, [age, 32.6 (24.2,43.9) years] were treated. 7 (12%) failed treatment and n=10 (18%) dropped out during the first 2 weeks of treatment due to palatability issues. In patients who completed 8 weeks of CD-TREAT course (n=40), 85% and 78% achieved clinical response and remission, respectively. CD-TREAT diet improved QoL in children [IMPACT-III score, baseline: 136 (122,143) vs 8weeks: 148 (133,153), p<0.01] and in adults [sIBDq score, baseline: 30 (26,45) vs 8weeks: 60 (48, 64), p<0.001]. Faecal GIP decreased during treatment [ng/g stool, baseline: 1250 (589, 1250), 4weeks: 0 (0,269), 8weeks: 0 (0,329), mg/mg, p<0.001 for both] showing adherence with the CD-TREAT diet. However, 33% and 40% of the patients had detectable faecal GIP at 4 and 8 weeks, respectively, revealing at least partial non-adherence. 30% of patients who completed CD-TREAT (n=12/40) experienced >50% FC reduction. Median FC levels decreased significantly? in the group of patients (n=22) who had undetectable GIP at 4 or 8 weeks [mg/kg FC, baseline: 1190 (361,1129); 8weeks: 534 (92,1230), p<0.01]. Conclusion CD-TREAT diet improved disease activity indices and QoL in the majority of patients who completed treatment and decreased FC in those who were most likely to be compliant. Future RCT should aim to compare CD-TREAT with other induction treatments and improve meal variety and palatability to improve compliance and reduce drop-out rates.

Visceral Hypersensitivity Is Provoked by 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Ileitis in Rats

Background and Aims: Crohn’s Disease (CD), a chronic Inflammatory Bowel Disease, can occur in any part of the gastrointestinal tract, but most frequently in the ileum. Visceral hypersensitivity contributes for development of chronic abdominal pain in this disease. Currently, the understanding of the mechanism underlying hypersensitivity of Crohn’s ileitis has been hindered by a lack of specific animal model. The present study is undertaken to investigate the visceral hypersensitivity provoked by 2,4,6-trinitrobenzene sulfonic (TNBS)-induced ileitis rats.Methods: Male Sprague-Dawley rats were anaesthetized and laparotomized for intraileal injection of TNBS (0.6 ml, 80 mg/kg body weight in 30% ethanol, n = 48), an equal volume of 30% Ethanol (n = 24), and Saline (n = 24), respectively. Visceral hypersensitivity was assessed by visceromotor responses (VMR) to 20, 40, 60, 80, and 100 mmHg colorectal distension pressure (CRD) at day 1, 3, 7, 14, 21, and 28. Immediately after CRD test, the rats were euthanized for collecting the terminal ileal segment for histopathological examinations and ELISA of myleoperoxidase and cytokines (TNF-α, IL-1β, IL-6), and dorsal root ganglia (T11) for determination of calcitonin gene-related peptide by immunohistochemistry, respectively.Results: Among all groups, TNBS-treatment showed transmural inflammation initially at 3 days, reached maximum at 7 days and persisted up to 21 days. The rats with ileitis exhibited (P < 0.05) VMR to CRD at day 7 to day 21. The calcitonin gene-related peptide-immunoreactive positive cells increased (P < 0.05) in dorsal root ganglia at day 7 to 21, which was persistently consistent with visceral hypersensitivity in TNBS-treated rats.Conclusion: TNBS injection into the ileum induced transmural ileitis including granuloma and visceral hypersensitivity. As this model mimics clinical manifestations of CD, it may provide a road map to probe the pathogenesis of gut inflammation and visceral hypersensitivity, as well as for establishing the therapeutic protocol for Crohn’s ileitis.

Nicotine InhibitsClostridium difficileToxin A-Induced Colitis but Not Ileitis in Rats

Nicotine is protective in ulcerative colitis but not Crohn's disease of the small intestine, but little is known about the effects of nicotine on Clostridium difficile toxin A-induced enteritis. Isolated ileal or colonic segments in anesthetized rats were pretreated with nicotine bitartrate or other pharmacological agents before intraluminal injection of toxin A. After 3 hours, the treated segments were removed and inflammation was assessed. Nicotine biphasically inhibited toxin A colitis but not ileitis. Pretreatment with the nicotinic receptor antagonist, hexamethonium, blocked the effects of nicotine. Pretreating the colonic segments with hexamethonium before toxin A administration resulted in more inflammation than seen with toxin A alone, suggesting that a tonic nicotinic anti-inflammatory condition exists in the colon. Nicotine also inhibited toxin A-induced increased colonic concentrations of the TRPV1 (transient receptor potential vanilloid subtype 1) agonist, leukotriene B4 (LTB4), and release of the proinflammatory neuropeptide, substance P. Pretreatment with nicotine did not protect against direct TRPV1-mediated colitis caused by intraluminal capsaicin. Nicotinic cholinergic receptors tonically protect the colon against inflammation and nicotine inhibits toxin A colitis but not toxin A ileitis in rats in part by inhibition of toxin A-induced activation of TRPV1 by endogenous TRPV1 agonists such as LTB4.

Simvastatin and Recombinant Antagonist of Receptors of Interleukin-1 Modulate Toll-like Receptors in Experimental Acute Ileitis in Rat

Background: The pathogenesis of inflammatory bowel disease is complex and multifactorial. Studies have led to the current concept that Toll-like receptors represent key mediators of innate host defense in the intestine, and they are involved in maintaining mucosal as well as commensal homeostasis. We studied the possibility of simvastatin and antagonist of receptors of interleukin-1 for pharmacological correction of acute ileitis in rats with a focus on the expression intensity studies of TLR2 TLR4 with lymphocytes of small intestine. Materials and Methods: Experiments were carried out on male Wistar rats aged 5–7 months (body mass 260–285 g). Rats were divided into four experimental groups: group 1 ― control; group 2 ― rats with indomethacin-induced ileitis; group 3 ― the rats were given simvastatin (20 mg/kg, for 5 days, subcutaneously); group 4 ―the rats had given antagonist of receptors of interleukin-1 (3 mg/kg, for 5 days, subcutaneously). The TLR2 and TLR4 immunopositive lymphocytes were determined using a direct immunofluorescence technique using a monoclonal rat antibody. Results: We established that development of ileitis was accompanied with the change of amount of TLR2 + and TLR4 + lymphocytes and the density of TLR2, TLR4 in immunopositive cells. Drug administration during the development of experimental pathology was accompanied by changes in the expression of TLR2, TLR4 and their density on lymphocytes. Conclusions: Simvastatin and antagonist of receptors of interleukin-1 seemed to be beneficial in indomethacin-induced rat ileitis model through modulate TLR2 and TLR4 expression with lymphocytes of small intestine.

Experimental model of rat ileitis resembling Crohn’s disease

Crohn’s disease (CD) is a chronic, idiopathic and relapsing inflammatory disease of the gastrointestinal (GI) tract. Current theories point to an impaired immune response to microbes within the intestinal flora in a genetically susceptible host. Although the lymphatic obstruction represents one of the main histopathological diagnostic criteria, its etiology is unknown. Many animal models that, in some respects, resemble human CD have been developed, but these models do not represent the complexity of human disease. We planned to obtain an animal model of CD by surgical manipulation of the enteric lymphatic vessels in the TNBS model of rat ileitis. Surgical approach: 12 F344 male rats were surgically treated by ligature and cut of ileo-colic lymphatic chain near the Treitz. The lymph nodes near the ileocecal valve were injected with a sclerosing agent (control group). Surgical and chemical approach: F344 were treated as above and, at the same time, intraluminally ileum injected with TNBS, a chemical reagent able to induce severe enteritis. 6 rats were sacrificed after one week (group 1). 8 rats received two more weekly TNBS injections and then were sacrificed (group 2). Control and treated rats were sacrificed at the same time. Animals were weighted and monitored for clinical manifestations of GI inflammation. At sacrifice, macroscopical changes were noted and ileum and colon specimens were harvested and processed for histopathological analysis. Most of the animals showed adhesions of bowel loops and thickening of the mesentery. Groups 1 and 2: TNBS induced more severe macroscopical features of inflammation in the intestinal wall, such as fistolae, dilatation of the ileum and sometimes intestinal obstruction. Microscopically, we observed transmural inflammatory infiltrate, fibrosis of mesentery, granulomas, and in the most severe cases, signs of neoangiogenesis, derangement of the muscle layers, ulcers and loss of villi in the mucosa. Besides the microscopical inflammatory changes, we evidenced an increased number of dilated lymphatic vessels. Group 1: one week after a single injection, most of the animals partially solved and showed less severe microscopical damages. The surgical and chemical approach did not induce in this rat model the severe fibrosis and the stricture of intestinal lumen that usually lead to surgery in human CD. However, the histopathological features found in these rats resemble the severe pathological features observed in human CD.

Bovine glycomacropeptide ameliorates experimental rat ileitis by mechanisms involving downregulation of interleukin 17

Bovine glycomacropeptide (BGMP) is an inexpensive, non-toxic milk peptide with anti-inflammatory effects in rat experimental colitis but its mechanism of action is unclear. It is also unknown whether BGMP can ameliorate inflammation in proximal regions of the intestine. Our aim was therefore two-fold: first, to determine the anti-inflammatory activity of BGMP in the ileum; second, to characterise its mechanism of action. We used a model of ileitis induced by trinitrobenzenesulphonic acid in rats. Rats were treated orally with BGMP and its efficacy compared with that of oral 5-aminosalicylic acid or vehicle, starting 2 days before ileitis induction. BGMP pretreatment (500 mg kg(-1) day(-1)) resulted in marked reduction of inflammatory injury, as assessed by lower extension of necrosis and damage score, myeloperoxidase, alkaline phosphatase, inducible nitric oxide synthase, interleukin 1beta, tumour necrosis factor and interleukin 17. These effects were generally comparable to those of 5-aminosalicylic acid (200 mg kg(-1) day(-1)). Neither compound affected the production of interferon gamma, tumour necrosis factor and interleukin 2 by mesenteric lymph node cells isolated from animals with ileitis. The expression of Foxp3 was increased in ileitis and not reduced significantly by BGMP or aminosalicylate treatment. These results demonstrate that BGMP has anti-inflammatory activity in the ileum with similar efficacy to 5-aminosalicylic acid. The mechanism of action may involve Th17 and regulatory T cells and perhaps macrophages but probably not Th1 lymphocytes. Patients with Crohn's ileitis may benefit from treatment with BGMP.

Differential Expression of Cannabinoid Receptors in the Human Colon: Cannabinoids Promote Epithelial Wound Healing

Differential Expression of Cannabinoid Receptors in the Human Colon: Cannabinoids Promote Epithelial Wound Healing

The Role of Leukotriene B 4 in Clostridium difficile Toxin A--Induced Ileitis in Rats

Clostridium difficile toxin A is a potent intestinal inflammatory agent that has been shown to act at least partially by neurogenic mechanisms involving activation of the transient receptor potential vanilloid 1 (TRPV1) (capsaicin) receptor. We tested the hypothesis that leukotriene B4 (LTB4) mediates the effects of toxin A via activation of the TRPV1 receptor. Isolated rat ileal segments were pretreated with pharmacologic agents before intraluminal injection of toxin A or LTB4. After 3 hours, the treated segments were removed and inflammation was assessed by luminal fluid accumulation, myeloperoxidase activity, and histology. LTB4 caused ileitis similar to that caused by toxin A and antagonism of TRPV1 receptors but not LTB4 receptors inhibited LTB4-induced inflammation. LTB4 also stimulated TRPV1-mediated substance P release and pretreatment with a specific substance P-receptor antagonist blocked LTB4-induced substance P action and ileitis. Inhibition of the LTB4 biosynthetic enzyme 5-lipoxygenase inhibited toxin A-induced increases in ileal LTB4 levels and toxin A- but not LTB4-induced ileitis. LTB4 mediates the inflammatory effects of toxin A via activation of TRPV1 receptors.

A novel diamino-pyridine derivative (IS-741) attenuates rat ileitis induced by trinitrobenzene sulfonic acid.

The etiology and pathogenesis of inflammatory bowel disease remain unknown. However, neutrophil infiltration into the inflammatory lesion is an important process in inflammatory bowel disease. In this study, we used rat trinitrobenzene sulfonic acid (TNBS) ileitis as a Crohn's disease model, and investigated the effects of oral IS-741 (which inhibits the expression of Mac-1, a cell adhesion molecule) on leukocyte-endothelial interactions. Rat ileitis was induced by the intraluminal injection of a TNBS solution (160 mg/kg in 50% ethanol) at a site 10 cm proximal to the ileocecal valve. The rats then received oral IS-741 (50 mg/kg) or saline for 7 days. On the day 8 after the initial administration of IS-741 or saline, we determined the visible damage score, and assessed myeloperoxidase (MPO) activity. Concentrations of cytokines in the ileum, such as interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) were assayed by enzyme-linked immunosorbent assay (ELISA). We also investigated the infiltration of polymorphonuclear cells and Mac-1 positive cells by histological examinations. The administration of IS-741 resulted in a significant reduction of the visible damage score, myeloperoxidase (MPO) activity, and mucosal IL-8 levels in the ileum as compared with the saline administration. IS-741 also dramatically reduced the infiltration of polymorphonuclear cells and Mac-1 positive cells into the inflamed lesions. These results indicate that the oral administration of IS-741 inhibits neutrophil infiltration into inflamed lesions, and is effective for attenuating rat TNBS ileitis. This new anti-inflammatory agent may be beneficial for the treatment of inflammatory bowel disease.

Impact on the bowel of amtolmetin guacyl, a new gastroprotective non-steroidal anti-inflammatory drug

Amtolmetin guacyl (MED15) is a new non-steroidal anti-inflammatory drug (NSAID) which shares anti-inflammatory, analgesic and antipyretic activity with the other drugs of the NSAID family but which shows, unexpectedly, strong gastroprotective activity similar to misoprostol. This effect has been attributed to the presence in its molecule of a vanillic moiety responsible for stimulation of capsaicin receptors present throughout the length of the gastrointestinal tract. MED15 shows antispasmodic activity in the bowel against a number of agonists and compares favourably with reference compounds. In in vivo indomethacin-induced rat ileitis, MED15 heals better than 5-aminosalicylic acid and sulfasalazine, as well as down-regulating intestinal wall myeloperoxidase content. In acetic acid-induced colitis in the rat, levels of malondialdehyde were found to be more markedly reduced with MED15 than with 5-aminosalicylic acid. In contrast with the effect in the stomach, MED15 protective effect in the bowel appears to be unrelated to nitric oxide (NO) production. The MED15 enteroprotective effect is related to stimulation of intestinal capsaicin receptors as demonstrated by the loss of protective effect in the presence of capsazepine, a specific receptor antagonist of capsaicin. In conclusion, following the favourable results obtained in animal models and notwithstanding the pharmacological effects typical of an NSAID, MED15 may rationally be proposed for the treatment of various human colitis conditions and Crohn's disease.

Mesenteric adipose tissue: A major source of TNFA in experimental ileitis in rats

Mesenteric adipose tissue: A major source of TNFA in experimental ileitis in rats

Characterization of M cell development during indomethacin-induced ileitis in rats.

M cells play an important role in the intestinal immune system as they have a high capacity for transcytosis of a wide range of microorganisms and macromolecules. However, little is known about the role of M cells during intestinal inflammation. We studied M cell development during indomethacin-induced intestinal inflammation in rats. Ileitis in rats was induced by two subcutaneous injections with indomethacin (7.5 mg/kg) given 24 h apart. Rats were sacrificed after 14 days and tissue was analysed by fluorescence microscopy and electron microscopy. M cells could be visualized by using the FITC-labelled mAb anti-cytokeratin (CK)-8 (clone 4.1.18), which was recently identified as specific M cell marker in rats. The number of cytokeratin-8 positive M cells was related to the surface of the follicle associated epithelium. For morphological studies, we used both transmission electron microscopy (T.E.M.) and scanning electron microscopy (S.E.M.). In non-inflamed ileum M cells were scarce. Only 4% of the follicle associated epithelium were M cells, whereas an increase of M cells up to 11% was found in inflamed follicle associated epithelium (P < 0.001). The rate of M cell induction depended on the macroscopic degree of inflammation. T.E.M./S.E.M. studies showed that in inflamed tissue most M cells underwent apoptosis with typical morphological signs. In contrast to apoptotic M cells, the neighbouring enterocytes usually appeared intact. The number of mononuclear cells below the follicle associated epithelium was significantly increased. S.E.M. studies revealed that during induced ileitis mononuclear cells migrated from the lamina propria into the gut lumen by passing through apoptotic M cells. During indomethacin-induced ileitis in rats the increase in M cell number in association with apoptosis of M cells may alter the intestinal barrier function. These observations may play a pivotal role in the pathogenesis of chronic intestinal inflammation, e.g. in inflammatory bowel disease.

Effect of anti-CD11b (alphaM-MAC-1) and anti-CD54 (ICAM-1) monoclonal antibodies on indomethacin induced chronic ileitis in rats.

Leukocyte emigration from blood to sites of inflammation involves sequential interaction of specific adhesion molecules expressed by both leukocytes and endothelial cells. The central steps in leukocyte-endothelial adhesive interactions are leukocyte rolling, sticking, and transmigration. This study investigated the effect of monoclonal antibodies against CD54 (ICAM-1) and CD11b (alphaM-chain of MAC-1) on intestinal inflammation. Anti-CD54 and anti-CD11b were tested in rats with indomethacin-induced chronic ileitis. Macroscopic changes were assessed by a modified version of the Wallace et al. score. Leukocyte rolling and sticking were investigated by intravital microscopy. Results show that indomethacin administration led to a chronic inflammatory response characterized by significant increase (P<0.05) in rolling (from 5.41+/-2.87 to 32.41+/-15.03 100 microm(-1) s(-1)) and sticking (from 0.16+/-0.18 to 9.11+/-5.3 100 microm(-1) s(-1)) leukocytes. After antibody treatment only the anti-CD11b group showed significant (P<0.05) reduction in rolling (from 32.41+/-15.03 to 6.6+/-2.7 100 microm(-1) s-1) and sticking (from 9.11+/-5.3 to 0.07+/-0.09 100 microm(-1) s-1) leukocytes. This was also the case for macroscopic changes. Indomethacin led to a rise in the Wallace score from 0 to 4.29+/-0.76 points (P<0.05) and anti-CD11b to a reduction from 4.29+/-0.76 to 1.29+/-1.11 points (P<0.05). Anti-CD54 and combined anti-CD11b/CD54 administration was not followed by significant changes. Therefore we suggest that leukocyte-based CD11b but not endothelial-based CD54 contributes most to leukocyte adhesion in the setting of indomethacin-induced ileitis in rats.

Participation of reactive oxygen metabolites in Clostridium difficile toxin A-induced enteritis in rats.

Reactive oxygen metabolites (ROMs) contribute to the pathophysiology of intestinal inflammation. Our aim was to ascertain the involvement of ROMs in experimental ileitis in rats produced by toxin A of Clostridium difficile. Intraluminal toxin A caused a significant increase in hydroxyl radical and hydrogen peroxide production by ileal microsomes starting 1 h following toxin exposure and peaking at 2-3 h, and this was inhibited by pretreatment with DMSO, a ROM scavenger, or superoxide dismutase (SOD), which inactivates ROMs. In contrast, mucosal xanthine oxidase increased only slightly after toxin A exposure, and allopurinol, an inhibitor of xanthine oxidase, had no effect on toxin A-associated intestinal responses. Induction of neutropenia resulted in reduction of toxin-mediated free radical formation, fluid secretion, and permeability. The enterotoxic effects of C. difficile toxin A were associated with increased ROM release in ileal tissues, and the ROM inhibitors DMSO and SOD inhibited these effects. This suggests that ROMs released during toxin A enteritis are released primarily from neutrophils invading the inflamed bowel segment.

Lectin binding sites in human intestinal M cells

threeto fourfold increase of M ceils (p<0.001). The rate of M cell induction strongly depended on the histological degree of inflammation. EM-studies showed that most M ceils changed their morphology compared to noninflamed mucosa with a strong increase of vacuoles in the cytoplasm and a complete lack of microfolds. The M cell surface often appeared desintegrated while the cytoplasm was usually well preserved. The number of mononuclear cells below the FAE was significantly increased. Discussion: The strong increase of M ceils during indomethacin induced ileitis in rats suggests an important role of M cells during chronic intestinal inflammation, e.g. in inflammatory bowel disease.

Induction of M cells in the indomethacin-induced ileitis in rats: Strong correlation with histological degree of inflammation

Induction of M cells in the indomethacin-induced ileitis in rats: Strong correlation with histological degree of inflammation

Leucocyte endothelial cell adhesion in indomethacin induced intestinal inflammation is correlated with faecal pH

Background—Recent studies indicate that faecal pH is acidified in patients with inflammatory bowel disease compared with healthy controls. In healthy volunteers, stool pH, faecal flora, and bile acid concentration could...

Acute and chronic effects of different bile acids on indomethacin-induced intestinal inflammation.

The role of bile acids in the pathogenesis of bowel inflammation is unknown. The objective of this study was to determine whether urso- (UDC), cheno- (CDC), and taurochenodeoxycholic acid (TCDC) exert a pro- or antiinflammatory action in the acute and chronic phase of the indomethacin model of a long lasting ileitis in rats. Short-term and long-term inflammatory responses (48 h and 10 days, respectively) after two subcutaneous indomethacin (Indo) injections were elicited in rat small bowel and mesentery. To distinguish between common and model-specific effects bile acids were tested also in another model of acute inflammation induced by mesenteric superfusion with leukotriene B4(LTB4). The number of adherent and emigrated leukocytes, leukocyte rolling velocity, and venular wall shear rate were monitored in normal and inflamed postcapillary venules, and fecal pH of ileal contents which has been shown to correlate with degree of inflammation was measured, 6.5- and 2.3-fold increases in leukocyte adherence and comparable increments in leukocyte emigration were observed 48 h and ten days after indomethacin treatment, respectively. UDC, CDC, and TCDC (10 mg/kg) given daily from Indo administration until the experiment attenuated the leukocyte adherence and emigration responses elicited by indomethacin in short- and long-term inflammation. This effect was accompanied by a significant increase of fecal pH which had been lowered by indomethacin. None of the bile acids reduced the LTB4-induced increases in adherence and emigration. Oral administration of UDC, CDC, and TCDC reduces leukocyte adhesion and emigration in acute and chronic stages of Indo-induced inflammation. This could be due to the alkalizing effect of these bile acids on fecal pH which has been shown to correlate with a decrease of leukocyte-endothelial cell interactions but--according to the missing effectiveness in another model of intestinal inflammation--not to specific influences on leukocyte-endothelial cell adhesion.

Role of interleukin 8 on leucocyte-endothelial cell adhesion in intestinal inflammation.

An important action of interleukin 8 (IL8) is stimulation of granulocytes. The object of this study was to assess the contribution of IL8 to the leucocyte-endothelial cell interactions associated with intestinal inflammation in the rat. Two indomethacin injections (48 and 24 hours prior to the experiments) induced a longlasting ileitis in rats. The number of adherent and emigrated leucocytes, leucocyte rolling velocity, and shear rate were monitored in normal and inflamed mesenteric postcapillary venules. Some animals received a monoclonal antibody (MAb) against IL8 or CD11b/CD18 at 24 and 12 hours prior to the experiment. Indomethacin elicited a seven-fold increase in leucocyte adherence and a 5.4-fold increase in leucocyte emigration, while leucocyte rolling velocity was reduced by nearly 80%. The indomethacin induced increases in leucocyte adherence and emigration were significantly reduced (by 57% and 67%, respectively) while leucocyte rolling velocity was increased (to 63% of control) by the IL8-specific MAb. The level of inhibition seen with the IL8 MAb was similar to that associated with administration of a MAb directed against the leucocyte adhesion molecule CD11b/CD18. IL8 contributes to the leucocyte-endothelial cell interactions elicited in mesenteric venules by indomethacin.