Pathophysiology Of Ulcerative Colitis Research Articles

W1316 Genetic Polymorphisms of Adhesion Molecules and the Effect of Granulocytapheresis Treatment for Ulcerative Colitis

[Background & Aims]The granulocytapheresis (GCAP) for ulcerative colitis (UC) has been developed in Japan. GCAP is a non-pharmacological therapy thereby does not have severe adverse effect. The mechanism of GCAP is expected to reduce inflammatory cytokines and the production of L-selectin by absorbing selected active granulocytes. Weakness of GCAP is the difficulty of the anticipation of treatment effect in early treatment stage. In this study, we focused on adhesion molecules which are thought to be associated with the pathophysiology of UC. We examined 5 SNPs in 3 adhesion molecule genes. [Methods] Twenty eight UC patients (M12, F16, averaged age 37.9y.o.) who received GCAP in past 5 years were examined. These patients were 21 pancolitis, 5 left sided colitis and 2 proctitis. DNA was extracted from all patients by colonic biopsy or blood sample and examined about the polymorphisms by PCR-RFLP. Genes and polymorphisms were L-selectin -642C>T and 725C>T, PECAM-1 codon125 V>L, E-selectin 98G>T in exon2 and S128R in exon4. The differences of the clinical activity index (CAI) scores of preand post-treatment of each 1 course (5 times of GCAP performed) or 2 course (10times of GCAP performed) were used for the evaluation of UC activity. Statistical analysis was done by Mann-Whitney U test. [Results] L-selectin-642C>T C carrier tended to be contributed to better treatment results after 2 course. L-selectin 725C>T polymorphism was not associated with treatment effect. PECAM-1 codon125 V>L, L/L or L/V was significantly associated with better treatment effect within 1 course treatment than V/V (p T and S128R polymorphisms showed no effect about GCAP treatment. [Conclusions] In this study, a significant effect of polymorphisms in PECAM-1 was found. Future study will be needed to confirm this result in next step.

W1317 Clinical Outcomes and Predictive Factors After the First Course of Corticosteroids in Patients With Active Ulcerative Colitis

[Background & Aims]The granulocytapheresis (GCAP) for ulcerative colitis (UC) has been developed in Japan. GCAP is a non-pharmacological therapy thereby does not have severe adverse effect. The mechanism of GCAP is expected to reduce inflammatory cytokines and the production of L-selectin by absorbing selected active granulocytes. Weakness of GCAP is the difficulty of the anticipation of treatment effect in early treatment stage. In this study, we focused on adhesion molecules which are thought to be associated with the pathophysiology of UC. We examined 5 SNPs in 3 adhesion molecule genes. [Methods] Twenty eight UC patients (M12, F16, averaged age 37.9y.o.) who received GCAP in past 5 years were examined. These patients were 21 pancolitis, 5 left sided colitis and 2 proctitis. DNA was extracted from all patients by colonic biopsy or blood sample and examined about the polymorphisms by PCR-RFLP. Genes and polymorphisms were L-selectin -642C>T and 725C>T, PECAM-1 codon125 V>L, E-selectin 98G>T in exon2 and S128R in exon4. The differences of the clinical activity index (CAI) scores of preand post-treatment of each 1 course (5 times of GCAP performed) or 2 course (10times of GCAP performed) were used for the evaluation of UC activity. Statistical analysis was done by Mann-Whitney U test. [Results] L-selectin-642C>T C carrier tended to be contributed to better treatment results after 2 course. L-selectin 725C>T polymorphism was not associated with treatment effect. PECAM-1 codon125 V>L, L/L or L/V was significantly associated with better treatment effect within 1 course treatment than V/V (p T and S128R polymorphisms showed no effect about GCAP treatment. [Conclusions] In this study, a significant effect of polymorphisms in PECAM-1 was found. Future study will be needed to confirm this result in next step.

Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis

Interleukin (IL)-33 is a cytokine belonging to the IL-1 family. IL-33 has been shown to elicit a Th2-like cytokine response in immune cells. In this study, we investigated IL-33 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD), and characterized the molecular mechanisms responsible for IL-33 expression in human colonic subepithelial myofibroblasts (SEMFs). IL-33 mRNA expression was determined by real-time polymerase chain reaction (PCR). IL-33 expression in the IBD mucosa was evaluated by immunohistochemical methods. IL-33 mRNA expression was significantly elevated in active lesions from patients with ulcerative colitis (UC), but was not detected in inactive lesions from UC patients or in lesions from patients with either active or inactive Crohn's disease. Colonic SEMFs were identified as a major source of IL-33 in the mucosa. IL-1β and tumor necrosis factor-α (TNF-α) significantly enhanced IL-33 mRNA and protein expression in isolated colonic SEMFs. IL-1β and TNF-α did not affect IL-33 expression in intestinal epithelial cell lines (HT-29 and Caco-2 cells). This IL-1β- and TNF-α-induced IL-33 mRNA expression was mediated by p42/44 mitogen activated protein kinase (MAPK) pathway-dependent activation of nuclear factor (NF)-κB and activator protein (AP)-1. IL-33, derived from colonic SEMFs, may play an important role in the pathophysiology of UC.

The Role of SAHA for Preventing IL-13-Induced Colon Epithelial Cell Dysfunction

IL-13 has been implicated as an effector cytokine in the pathophysiology of ulcerative colitis (UC) through increasing colon epithelial cell apoptosis and expression of the pore-forming tight junction protein claudin-2. Binding of IL-13 to its receptor leads to activation of STAT6. The STAT6 phosphorylation status in patients with UC, however, is unknown, as is the effect of STAT6 inhibition on colonic epithelium exposed to IL-13. Suberoylanilide hydroxamic acid (SAHA) is a FDA-approved histone deacetylase inhibitor that inhibits constitutive STAT6 activation in lymphoma cell lines. Therefore, the aim of this study was to determine if STAT6 phosphorylation is increased in patients with UC, and if inhibition of STAT6 signaling with SAHA attenuates IL-13-induced apoptosis and claudin-2 expression. To assess IL-13 signaling, immunohistochemical staining for phosphorylated (p) STAT6 was performed on colonic tissue from pediatric subjects with UC (early UC, n= 10) and Crohn's disease (CD, n= 10) at diagnosis, colectomy tissue from adults with UC (late UC, n= 5) and controls (n= 10). A pathologist blinded to the diagnosis scored histological sections on a 0-4 scale for pSTAT6. In cell culture, human colon HT-29 cells were pre-treated with SAHA (1 or 5 μM) or vehicle control prior to treatment with IL-13 (10 ng/ml). Western blot analysis was performed on cellular lysates for pSTAT6 and claudin-2 with results quantified by densitometry. Apoptosis was determined by flow cytometry of Annexin V-PE-stained cells and by immunodetection of cleaved caspase-3. Epithelial pSTAT6 staining was increased in UC with median score of 0 in control subjects, 2 in early UC (vs. control P= 0.004), 4 in late UC (P= 0.014), and 0 in CD. In HT-29 cell culture, SAHA inhibited IL-13-induced pSTAT6 in a dose-dependent fashion with a 57% reduction of pSTAT6 induction at 5 μM (P < 0.01). IL-13 induced a 2-fold increase in claudin-2 expression (p < 0.05), and SAHA reduced IL-13-induced claudin-2 expression by 70% to baseline levels (p<0.05). By Annexin V staining, IL-13 increased apoptosis 2.7-fold (3.7 ±1.6% vs. 10.0±1.4% Annexin V+, P<0.01). SAHA alone did not increase apoptosis and reduced IL-13-induced apoptosis in a dose-dependent manner with complete suppression to baseline at 5 μM (IL-13 + SAHA 1 μM 7.5±0.8%, + 5 μM 4.8±0.9, Ptrend< 0.001). Similarly, by immunodetection of cleaved caspase-3, SAHA reduced IL-13 induced apoptosis by 57% at 1 μM and 94% at 5 μM (P<0.001 for each compared to IL-13 alone). Increased STAT6 phosphorylation in the colonic epithelium of pediatric subjects at presentation with UC supports an effector role of IL-13 early in the disease. Treatment of colonic epithelial cells with SAHA, a drug that inhibits IL-13-induced STAT6 activation, reduces IL-13-induced apoptosis and claudin-2 expression, suggesting that STAT6 may be a novel therapeutic target for UC.

Arthritis Associated with Ulcerative Colitis: Our Experience in Palermo

To The Editor: Ulcerative colitis (UC) is one of the inflammatory bowel diseases, which affects the small intestine and colon [1]. The pathophysiology of UC is not known [2, 3]. The association between arthritis and UC is well known. The authors report the frequency of arthritis in 53 Sicilian patients with UC. The diagnosis of UC was made according to criteria described by Schachter and Kirsner [4]. The involvement of sacroilitic joints was assessed radiologically according to Bennett and Burch grade (0=normal joint, 1=suspicious sacroiliitis 2=abnormal joint with sclerosis and/or erosions, 3=unequivocally abnormal with erosions, sclerosis, widening or narrowing or partly ankylosed, 4=total ankylosis) [5]. All patients were screened for the presence of the antigen HLA B27. Arthritis occurred in 11 patients (20.7%). Patients with arthritis had high erythrocyte sedimentation rate (>20) and high C-reactive protein (mean value 14mg/L) at presentation. Latex fixation test rheumatoid factor (RF) was negative in all except one patient who had monoarticular knee involvement (RF = 45 IU/ml). Peripheral arthritis was found in 9 patients (17%). Only three patients had polyarticular involvement. The joints involved in peripheral arthritis were most frequently the knee joint (4 patients), followed by the ankle (3 patients), elbow (2 patients), wrist (2 patients), proximal interphalangeal (2 patients), shoulder (1 patient), and the hip (1 patient). Spondylitis was diagnosed in 2 patients (3.8%), one with sacroilitis grade 2 and the other with grade 3. Both patients with sacroilitiis showed positive HLA B27. In conclusion, our observation of the association between UC and arthritis is in line with previous reports in the literature [6, 7]. The basis of this association is unknown. A better understanding of the role of genetics and environmental factors may improve the treatments and prevention of the disease.

A Meta-Analysis of the Efficacy of Sulfasalazine in Comparison with 5-Aminosalicylates in the Induction of Improvement and Maintenance of Remission in Patients with Ulcerative Colitis

Historically, sulfasalazine (SSZ) and 5-aminosalicylates (5-ASAs) have been a mainstay of mild-to-moderate ulcerative colitis (UC) remission induction and maintenance therapy. Considering the pivotal role of intestinal microbial flora in pathophysiology of UC and antimicrobial activity of sulfapyridine, we hypothesized that SSZ might be more effective than 5-ASAs in the management of UC. To compare the efficacy and tolerability of SSZ with each of the 5-ASAs (mesalamine, olsalazine, and balsalazide) by a meta-analysis technique. Pubmed, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials were searched for studies compared efficacy and/or tolerability of SSZ with 5-ASAs in the management of UC. The search terms were: "sulfasalazine" or "sulfasalazine" and "5-aminosalicylic acid," "mesalazine," "mesalamine," "olsalazine" or "balsalazide" and "ulcerative colitis." Data were collected from 1966 to April 2008. There was no language restriction. "Overall improvement," "relapse rate," "total adverse events," and "withdrawals because of adverse events" were the key outcomes of interest. Twenty randomized placebo controlled trials met our criteria and were included in the meta-analysis. Comparison of SSZ with mesalamine yielded a nonsignificant relative risk (RR) of 1.04 (95% confidence interval of 0.89-1.21, P = 0.63) for overall improvement, a nonsignificant RR of 0.98 (95% CI 0.78-1.23, P = 0.85) for relapse, a nonsignificant RR of 0.76 (95% CI 0.54-1.07, P = 0.11) for any adverse events, and a nonsignificant RR of 0.78 (95% CI 0.46-1.3, P = 0.33) for withdrawals due to adverse events. Comparison of SSZ with olsalazine yielded a nonsignificant RR of 1.14 (95% CI 0.91-1.43, P = 0.25) for overall improvement, a nonsignificant RR of 0.93 (95% CI 0.77-1.12, P = 0.42) for relapse, a nonsignificant RR of 1.21 (95% CI 0.9-1.61, P = 0.20) for any adverse events, and a nonsignificant RR of 1.53 (95% CI 0.93-2.52, P = 0.09) for withdrawals due to adverse events. Comparison of SSZ with balsalazide yielded a nonsignificant RR of 1.3 (95% CI 0.93-1.81, P = 0.12) for overall improvement, and a significant RR of 0.17 (95% CI 0.06-0.49, P = 0.001) for withdrawals because of adverse events. SSZ does not differ from mesalamine or olsalazine in terms of efficacy and tolerability in UC. Withdrawal from study due to adverse events was significantly lower for balsalazide compared with SSZ. Convincing conclusions on the comparison of effectiveness and safety of balsalazide and SSZ in UC remains to be elucidated by further clinical trials. Considering the lower cost of treatment with SSZ and the equal rate of adverse events with other 5-ASAa, it is not surprising to suggest SSZ as a first-choice treatment for UC and reserve 5-ASAs for when SSZ intolerability occurs.

Five mucosal transcripts of interest in ulcerative colitis identified by quantitative real-time PCR: a prospective study

BackgroundThe cause and pathophysiology of ulcerative colitis are both mainly unknown. We have previously used whole-genome microarray technique on biopsies obtained from patients with ulcerative colitis to identifiy 5 changed mucosal transcripts. The aim of this study was to compare mucosal expressions of these five transcripts in ulcerative colitis patients vs. controls, along with the transcript expression in relation to the clinical ulcerative colitis status.MethodsColonic mucosal specimens from rectum and caecum were taken at ambulatory colonoscopy from ulcerative colitis patients (n = 49) with defined inflammatory activity and disease extension, and from controls (n = 67) without inflammatory bowel disease. The five mucosal transcripts aldolase B, elafin, MST-1, simNIPhom and SLC6A14 were analyzed using quantitative real-time PCR.ResultsSignificant transcript differences in the rectal mucosa for all five transcripts were demonstrated in ulcerative colitis patients compared to controls. The grade of transcript expression was related to the clinical disease activity.ConclusionThe five gene transcripts were changed in patients with ulcerative colitis, and were related to the disease activity. The known biological function of some of the transcripts may contribute to the inflammatory features and indicate a possible role of microbes in ulcerative colitis. The findings may also contribute to our pathophysiological understanding of ulcerative colitis.

The proinflammatory CXC-chemokines GRO-α/CXCL1 and MIG/CXCL9 are concomitantly expressed in ulcerative colitis and decrease during treatment with topical corticosteroids

Ulcerative colitis is characterized by relapsing mucosal inflammation where the lesions include tissue-damaging granulocytes. In addition, T cells and natural killer (NK) cells play important pathophysiologic roles. Chemokines are a large family of peptides that play key roles in the regulation of inflammation. The CXC-chemokines, growth-related oncogene (GRO)-alpha/CXCL1 and interleukin (IL)-8/CXCL8, both recruit neutrophils and possess mitogenic properties, whereas the interferon-dependent CXC-chemokines monokine induced by gamma-interferon (MIG)/CXCL9, interferon-gamma inducible protein of 10 kD/CXCL10, and IFN-inducible T cell alpha chemoattractant/CXCL11 recruit and activate T cells and NK cells. The expression of CXC-chemokines was studied in eight controls and in 11 patients suffering from ulcerative colitis in the distal part of the colon, before and during topical treatment with corticosteroids. Perfusates (obtained before, after 7 days, and after 28 days of treatment) and pinch biopsies (obtained before and after 28 days of treatment) were collected by colonoscopy. The rectal release of GRO-alpha and MIG was determined by enzyme-linked immunosorbent assay (ELISA), and tissue expression of the chemokines was detected in colonic tissue by immunohistochemistry. In perfusates, high levels of GRO-alpha, IL-8, and MIG were detected compared with controls (p=0.02, 0.005, and p=0.03, respectively). During treatment with corticosteroids, both GRO-alpha and MIG decreased. In clinical nonresponders, characterized by sustained inflammation, the levels of GRO-alpha and MIG remained elevated. Both epithelial cells and granulocytes, present in the submucosa, expressed GRO-alpha and MIG as detected by immunohistochemistry. CXC-chemokines are likely to be important in the pathophysiology of ulcerative colitis and may become targets for novel treatment strategies. In addition, GRO-alpha may serve as a marker of disease activity.

Expression of the REG IV gene in ulcerative colitis

The regenerating gene (REG) IV gene was isolated from a cDNA library of ulcerative colitis (UC) tissues. However, its role in the pathophysiology of UC and subsequent development of colitic cancer is still unclear. We investigated the expression of the REG IV gene in UC and colitic cancer tissues and examined whether cytokines or growth factors are responsible for REG IV gene expression and whether REG IV gene induction affects cell growth and apoptosis in colon cancer cells. The expressions of REG IV and growth factor genes in UC tissues were analyzed by real time reverse transcription-polymerase chain reaction. The effects of cytokines and growth factors on REG IV gene expression were examined in SW403 cells by Northern blot analysis. The effects of REG IV gene induction on cell growth and H2O2-induced apoptosis were examined in DLD-1 cells by MTT and TUNEL assays, respectively. REG IV mRNA was strongly expressed in inflamed epithelium and in dysplasias and cancerous lesions in UC tissues. The level of REG IV mRNA expression was correlated with that of basic fibroblast growth factor (bFGF) as well as hepatocyte growth factor (HGF) mRNA expression in UC tissues. The REG IV gene expression in SW403 colon cancer cells was enhanced by stimulation with transforming growth factor-α, epidermal growth factor, bFGF, and HGF. REG IV gene induction promoted cell growth and conferred resistance to H2O2-induced apoptosis in DLD-1 cells. The REG IV gene is inducible by growth factors and may function as a growth promoting and/or an antiapoptotic factor in the pathophysiology of UC.

Substance P and the neurokinin-1 receptor in relation to eosinophilia in ulcerative colitis

Substance P (SP) has been implicated in the pathophysiology of ulcerative colitis (UC) and it has been suggested that blocking of its effect would be advantageous in this disease. Eosinophils have also been implicated in the pathophysiology of UC. In the present study, specimens from the sigmoid colon of UC patients were investigated by the use of antisera against SP and the neurokinin-1 receptor (NK-1R) and staining for demonstration of eosinophils. The degrees of SP innervation and NK-1R immunoreaction, as well as the levels of eosinophil infiltration, varied between different patients. Interestingly, NK-1R immunoreaction in the epithelium was often seen to be the most marked where there were numerous eosinophils in the underlying mucosa and where the mucosa showed a marked morphologic derangement. The observations suggest that there are marked fluctuations in effects of SP and eosinophils during the disease. The infiltrating eosinophils may be involved in the destruction of the mucosal tissue. Furthermore, for the majority of cases where there is marked derangement of the mucosa, it is apparent that there is an upregulation of the NK-1 receptor in the epithelium in parallel with the infiltration of the eosinophils.

Update on the pathophysiology of inflammatory bowel disease

Crohn's disease (CD) and Ulcerative colitis (UC) comprise a series of inflammatory bowel disease (IBD) resulting from chronic up-regulation of the mucosal immune system. Although the pathogenesis of IBD remains elusive, it appears that there is chronic activation of the immune and inflammatory cascade in genetically susceptible individuals, which are directed by genetic factors, immunological factors, and environmental factors such as foods and enteric microbes. Regarding genetic factors, important new insights have been gained into the function of caspase-activating and recruitment domain-15 (CARD15)/NOD2, the first cloned susceptibility gene for CD. New data on CARD15/NOD2 function and nuclear factor-κB activation indicate that an inflammatory reaction of the intestinal mucosa as a response of the innate immune system may be necessary for the maintenance of gut homeostasis. CD may therefore be seen as a defective immune response, no longer only as hyperresponsiveness of the mucosal immune system. Data on CARD15/NOD2 expression suggest that macrophages and epithelial cells could be the site of a primary pathophysiologic defect, and T-cell activation might just be a secondary effect inducing chronification of the inflammation, perhaps as a backup mechanism to a defective innate immunity. In addition to CARD15/NOD2, there are additional “innate” pathways by which commensal and pathogenic bacteria can directly interact with cells of the intestinal mucosa (eg, toll-like receptors). The “germ concept” and the “genetic concept” of IBD pathophysiology are converging. The evidence continues to accumulate that CD is primarily due to a T helper cell-type 1 immune response in the gut wall. IL-12 and IL-18 appear to be the cytokines primarily responsible for Th1 polarization. T-cell resistance to apoptosis occurs in CD, and human and mouse studies indicate that the signaling molecule STAT3, which transduces signals from IL-6 and IL-10, is involved in mucosal T cell homeostasis. Progress in understanding the pathophysiology of UC remains slow, but IL-13 produced by natural killer T cells may be involved. There is a possibility that UC might be a sort of syndrome such as viral/bacterial infectious diseases and autoimmune disorders. Despite the evidence of a role for Th1 in CD, support for a Th2 pathogenesis in ulcerative colitis is much weaker. The presence of autoantibodies, such as anticolon antibody, antimucin antibody, or antitropomyosin antibody, is suggestive of a Th2 pathogenesis. There are several conflicting immunological findings, but some immunological abnormalities may induce colonic inflammation.

Ulcerative colitis—Diagnosis and surgical treatment

Ulcerative colitis is a serious illness affecting the colon. Extracolonic manifestations include sclerosing cholangitis, arthritis, eye diseases, ankylosing spondylitis, and sacroiliitis. Ulcerative colitis may increase a patient's risk of cancer, depending on the duration and extent of the disease. Surgery is the only definitive way to remove the disease in its entirety. It may be possible for patients who do not wish to have a permanent stoma to undergo a restorative proctocolectomy with ileal pouch-anal anastomosis. Normal bowel physiology, pathophysiology of ulcerative colitis, medical and surgical treatments, and postoperative complications are discussed.

Total antioxidant capacity of colon in patients with chronic ulcerative colitis.

It has been proposed that oxidative stress is involved in the pathophysiology of ulcerative colitis. We have reported the depletion of the nonenzymatic antioxidant, glutathione, in colon from active and inactive ulcerative colitis. The colon contains several biochemically linked antioxidant systems. We hypothesized that diminished total antioxidant capacity in active ulcerative colitis would be associated with increased colonic lipid peroxidation. This study was designed to determine total antioxidant capacity and lipid hydroperoxide levels using colon obtained at surgery from controls (N = 16; 4 females, 12 males; mean age 70 years), and active and inactive ulcerative colitis (N = 15; 3 females, 12 males; mean age 39). Total antioxidant capacity of control colon was higher in muscularis externa compared to the mucosal-submucosal layer (P < 0.05). There were no differences in colonic total antioxidant capacity or lipid hydroperoxide levels comparing control colon to inactive and active ulcerative colitis. The results did not support depletion of tissue total antioxidant capacity by free radicals. Depletion of glutathione in ulcerative colitis may be a specific disorder rather than a secondary defect attributable to global oxidative stress. Nonspecific antioxidant supplements appear unlikely to be beneficial in the treatment of ulcerative colitis.

Diosmectite for Ulcerative Colitis

The aetiology of ulcerative colitis remains obscure, despite intensive investigation. Since damage is confined to the mucosa, luminal factors may play a pathogenetic role. In particular, the mucus gel covering the colonic epithelium provides a physical barrier against microorganisms, toxins, allergens and damaging factors.[1] Consequently, colonic mucus breakdown can be a factor in the pathophysiology of ulcerative colitis. Indeed, faecal proteinase activity, which indicates enzymatic degradation of adherent colonic mucus,[2] appears to be increased in ulcerative colitis.[3,4] This is consistent with the report of a significant reduction in the colonic mucus thickness in biopsies of subjects with ulcerative colitis.[5] Agents able to strengthen the colonic mucus barrier and to inhibit intestinal proteinase activity may be of therapeutic value in the disease. Diosmectite is an insoluble double silicate of aluminium and magnesium, which binds to mucus in vitro and in vivo[6] and inhibits faecal proteinase activity from both control and colitic faecal extracts (H.J.I. Samson et al., unpublished data). In addition, the clay appears to exert anti-inflammatory activities at the luminal site of intestinal epithelium.[7] Although diosmectite has been shown to be effective as an anti-diarrhoeal agent,[8,9] its possible effect in ulcerative colitis has not been determined. The aim of the present, preliminary, pilot study was to investigate the possible therapeutic effect of diosmectite in patients with ulcerative colitis of mild to moderate degree. Patients and Methods

Platelet activating factor: release from colonic mucosa in patients with ulcerative colitis and its effect on colonic secretion.

Inflammatory mediators have been implicated in the pathophysiology of ulcerative colitis. They may stimulate intestinal secretion and contribute to the production of diarrhoea. Platelet activating factor (PAF) may be responsible for a high proportion of this secretory response. Biopsy specimens from inflamed and quiescent mucosa of patients with ulcerative colitis and normal human colonic mucosa were cultured or co-cultured. The release of PAF, prostaglandin E2, and leukotriene D4 into the culture medium was measured and the ability of this culture medium, from inflamed and normal tissues, to influence secretion in rat colonic mucosa was assessed. PAF was liberated by inflamed tissue. Its release from quiescent but not normal tissue was stimulated by medium in which inflamed mucosal biopsy tissues had been cultured and by exogenous bradykinin and 5-hydroxytryptamine, but not by histamine. PAF stimulated eicosanoid production. The rise in short circuit current produced in vitro by inflamed tissue culture medium was inhibited by the PAF receptor antagonist (CV 6209) (46%) (32.4 (2.9) v 17.5 (1.19) muA.cm-2, p < 0.005) and further by combined cyclooxygenase and lipoxygenase inhibition (indomethacin plus ICI 207968) (58%) (32.4 (2.9) v 13.6 (1.9) muA.cm-2, p < 0.005). Mepacrine and hydrocortisone attenuated considerably the electrical response evoked by medium from inflamed mucosa to a similar extent (32.4 (2.9) v 6.3 (1.2) v 5.1 (0.9) muA.cm-2, p < 0.001). These data suggest that PAF accounted for 46% of the culture medium secretory effect. Thus, any attempt to block its release in patients with ulcerative colitis may have only a partial effect on their symptoms.

Inhibitory effects of azelastine and tranilast on leukotriene B 4 and leukotriene C 4 generation by rat colonic mucosa

Anti-allergic drugs such as sodium cromoglycate are known to be effective for the treatment of ulcerative colitis (UC). Because leukotriene (LT) production is considered to play an important role in the pathophysiology of UC, we examined the effect of the anti-allergic drugs, azelastine and tranilast, and the 5-lipoxygenase inhibitor, AA861, on LTB 4 and LTC 4 production by isolated rat colonic mucosa treated with the calcium ionophore, A23187. Preincubation of colonic mucosa with AA861 (10 −4 M) or azelastine (10 −4 M) significantly reduced AA23187-induced LTB 4 ( p < 0.01 and p < 0.05, respectively) and LTC 4 ( p < 0.01) production. Pretreatment with tranilast (10 −3 M) also significantly reduced A23187-induced LTC 4 production ( p < 0.05). These findings suggest that azelastine and tranilast can inhibit LT production in colonic mucosa and may be beneficial in the treatment of patients with UC.

Inflammatory bowel disease in children.

Inflammatory bowel disease remains a serious chronic illness in children. Recent developments in the care of these patients involves both basic science research into the pathophysiology of ulcerative colitis and Crohn's disease and the development of refinements in the surgical techniques and medical therapies available as treatment options. In Crohn's disease, a new steroid analogue (budesonide) shows some promise as a possible medical treatment that would limit the devastating side effects of steroids in children. In addition, the bowel-sparing technique of strictureplasty has now been reported in children with good results. In ulcerative colitis, the surgical technique of endorectal pull-through continues to evolve with reports of the efficacy of specific pouch designs and surgical techniques. An understanding of pouchitis, the most common complication of endorectal pull-through, has focused on documenting specific alterations in the microbiology and physiology of the pouch, as well as investigating a possible link between autoantibodies and susceptibility to this complication.

Pathophysiology of ulcerative colitis: Possible role for novel colonic factors that modulate neutrophil function: [formula omitted], J Fields, S Sedghi, D Eiznhamer, D Winship, A Keshavarzian. Depts Med & Pharm, Loyala Med Sch, Maywood IL; Med & Res Svces, VAH, Hines IL

Pathophysiology of ulcerative colitis: Possible role for novel colonic factors that modulate neutrophil function: [formula omitted], J Fields, S Sedghi, D Eiznhamer, D Winship, A Keshavarzian. Depts Med & Pharm, Loyala Med Sch, Maywood IL; Med & Res Svces, VAH, Hines IL

Potential Role for Interleukin-1 in the Pathophysiology of Ulcerative Colitis

1. Biopsies of colonic mucosa from patients with ulcerative colitis liberated more interleukin-1 beta, prostaglandin E2, leukotriene C4 and platelet-activating factor into the medium in which they were cultured than biopsies from patients with irritable bowel syndrome and histologically normal mucosa. 2. Addition of interleukin-1 stimulated release of greater quantities of all these inflammatory mediators, including interleukin-1 itself, from inflamed and normal mucosa. 3. Blockade of cyclo-oxygenase with indomethacin or of lipoxygenase with ICI 207968 or of phospholipase A2 with mepacrine inhibited release of prostaglandin E2 or leukotriene C4 or both of these plus platelet-activating factor, respectively. 4. Interleukin-1 stimulated the short-circuit current across isolated rat colonic mucosa mounted in flux chambers in a dose-dependent manner (Km 2 x 10(-11) mol/l). This stimulation was markedly inhibited by the removal of chloride from the bathing media. 5. Indomethacin or ICI 207968 inhibited the short-circuit current response to interleukin-1 and a combination of these antagonists produced a greater inhibition. Mepacrine caused an even greater inhibition whereas tetrodotoxin plus mepacrine inhibited the current completely. 6. These data indicate that interleukin-1, released in excess from inflamed colonic mucosa, stimulates the release of a range of inflammatory mediators as well as of more interleukin-1. It probably acts by stimulating phospholipase A2 in inflammatory cells, probably lymphocytes, and can do so in normal and inflamed mucosa. Since, in rat colonic mucosa it stimulated an electrical response in very low concentrations, it is feasible that it is involved in the chloride secretion, and hence the diarrhoea, which may occur in inflammatory reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

High concentration and retained amidation of fecal bile acids in patients with active ulcerative colitis.

Fecal bile acid profiles of 14 patients with ulcerative colitis in the active phase were analyzed to study the potential significance of bile acids in the pathophysiology of this disease, and the results were compared with those in 12 healthy controls. The excretion levels of total bile acids (mean +/- SD) in patients were higher than in controls, 445.1 +/- 392.1 vs 215.5 +/- 148.0 mumol/day, 3.1 +/- 1.7 vs 1.6 +/- 1.0 mumol/g wet feces (P less than 0.05), and 17.2 +/- 9.2 vs 12.4 +/- 13.3 mumol/g dry feces. Fecal profiles of individual bile acids showed higher levels of primary bile acids (52 +/- 27%) in patients compared to those (26 +/- 21%) in controls. Proportions of glycine and taurine conjugates in patients (26 +/- 24%) were higher than in controls (5 +/- 2%) (P less than 0.05), whereas proportions of unconjugates and sulfates were lower in patients than in controls. Accordingly the extent of deconjugation and dehydroxylation of bile acids was lower in patients than in controls. These trends were prominent in patients with more severe disease activity. A high concentration of bile acids in the intestine may have a significant role in the pathophysiology of ulcerative colitis at active phase.