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PubMed1987

Studies on the mechanism of bowel disturbance in ulcerative colitis.

The transit of a radiolabeled meal through the gastrointestinal tract and stool output were measured in 62 patients with ulcerative colitis, subdivided according to the activity and extent of their disease. The results were compared with those from 20 sex-matched normal subjects. Mouth-to-cecum transit was significantly slower than normal in all patient groups although gastric emptying was normal. Whole gut transit was not accelerated in any group of patients. An abdominal x-ray taken 48 h after ingesting the meal showed that patients with active colitis had proximal colonic stasis, whereas transit through the rectosigmoid region was rapid. Stool weights and frequencies were higher in patients with active colitis than in patients with quiescent disease. Patients with active colitis also passed smaller amounts of stool during each bowel movement, suggesting that they experienced a desire to defecate at lower rectal volumes. These results indicate that (a) diarrhea in ulcerative colitis is associated with rectosigmoid irritability rather than rapid transit and (b) caution should be used when treating active colitis with antidiarrheal drugs that could further retard proximal colonic transit.

Colitis, Ulcerative↗
PubMed1987

Prostaglandin regulation of colonic blood flow in rabbit colitis.

Human and experimental colitis are associated with release of both vasoconstrictor and vasodilator eicosanoids. To determine the pattern of colonic blood flow in vivo and the role of prostaglandins and thromboxanes, immune complex-mediated colitis and delayed hypersensitivity-mediated colitis were induced in rabbits. Organ blood flow was determined in conscious animals by radiolabeled microspheres before and after cyclooxygenase or thromboxane synthetase inhibition. Colonic blood flow was twofold higher in colitis than in control animals. Thromboxane synthetase inhibition with dazoxiben caused a slight further increase of colon perfusion in animals with colitis, but thromboxane receptor blockade had no effect. Prostaglandin inhibition with indomethacin and ibuprofen did not affect blood flow in controls, but in animals with colitis these drugs markedly reduced colonic blood flow to the level of control animals. The data demonstrate that vasodilatory prostaglandins enhance colonic blood flow in acute colon inflammation.

Animals↗
PubMed1988

Spontaneous contractions and some electrophysiologic properties of circular muscle from normal sigmoid colon and ulcerative colitis.

Spontaneous contractions, inhibitory responses produced by electrical field stimulation, and some electrophysiologic properties of circular smooth muscle from normal sigmoid colon and from sigmoid colon of ulcerative colitis patients were compared in vitro using simultaneous recordings of mechanical and intracellular electrical activity. In normal colonic circular muscle obtained from 21 patients, the frequency of spontaneous summation contractions ranged from 3 to 7 per 4 min, whereas in circular muscle from 13 patients with ulcerative colitis, the frequency of these contractions ranged from 1 to 9 per 4 min. Nonadrenergic, noncholinergic relaxation produced by electrical field stimulation was recorded in the majority of circular smooth muscle strips from both normal colon and colon from patients with ulcerative colitis. There were no significant differences in mean resting membrane potential, mean slow-wave frequency, mean maximum slow-wave amplitude, or inhibitory-junction potential amplitudes recorded using circular smooth muscle from both normal colon and colon from patients with ulcerative colitis. There appeared to be a weak association in patients with ulcerative colitis between increasing duration of symptoms and decreasing frequency of spontaneous summation contractions, but there were no associations between the frequency of these contractions and the severity of colonic inflammation, patient age, or the frequency of stools. The mechanism accounting for a wider range in the frequency of summation contractions recorded from colonic circular smooth muscle in ulcerative colitis remains to be determined.

Adult↗
PubMed1988

Emergence of antigenic glycoprotein structures in ulcerative colitis detected through monoclonal antibodies.

The emergence of new glycoprotein structures in colonic mucosa from patients with ulcerative colitis (UC) was assessed through the development of monoclonal antibodies (MAbs). Hybridomas were prepared from mice immunized with mucin glycoproteins purified from UC colonic tissue. Supernatants of 11 fusion products among 1200 fusion products that were screened in a solid-phase binding assay differentially bound UC-derived colonic mucin glycoproteins relative to comparable preparations from normal or Crohn's colitis tissue. These hybridomas were double-cloned to yield MAbs designated as MAbs UC 1-11. Disease-related specificity of MAbs UC 1-11 was determined through assessment of binding to beads coated with mucin glycoproteins purified from individual samples of UC tissue (n = 15), normal tissue (n = 21), and Crohn's colitis tissue (n = 10). Monoclonal antibody UC 7, an MAb of immunoglobulin G2A subclass, showed differential binding in solid-phase assays to UC mucin glycoproteins, with a mean binding of 10,170 +/- 2740 cm per UC glycoprotein-coated bead versus 2300 +/- 1080 and 2470 +/- 1525 cpm for normal and Crohn's colitis-derived glycoproteins, respectively. Monoclonal antibody UC 11 showed similar differential binding to UC mucin glycoproteins (9860 +/- 680 cpm vs. 1770 +/- 420 cpm). Binding specificity in solid-phase assay was mirrored by colonic mucosal staining patterns assessed by indirect immunofluorescent staining. Monoclonal antibody UC 7 specifically stained colonic mucosa from 8 of 10 patients with active UC, none of the samples from 8 normal controls, and none of the samples from 11 disease controls (six with Crohn's colitis, five with other inflammatory disorders). Specific staining was present on both the epithelial surface and on cells scattered within the lamina propria. Staining by MAb UC 7 was also observed in 3 of 4 samples of proximal uninvolved mucosa from patients with left-sided ulcerative colitis and in 3 of 5 samples from UC patients without acute disease activity.

Animals↗
PubMed1990

Lack of association between oral contraceptive use and ulcerative colitis.

Previous epidemiological studies suggesting an association between oral contraceptive use and ulcerative colitis incidence have been weak and conflicting. To measure a possible association, 46 incident cases of ulcerative colitis patients, women aged 18-50 years, were compared with peer-nominated age-matched and sex-matched controls. There were no differences between case and control patients in demographic characteristics. There was no association between oral contraceptive use and ulcerative colitis (current use: odds ratio 0.70, 95% confidence interval 0.27-1.83; former use: odds ratio 1.14, confidence interval 0.41-3.15; current or former use: odds ratio 0.86, confidence interval 0.40-1.85). Stratifying by disease location (pancolitis or left-sided disease) also failed to identify an association. Controlling for possible confounding effects of cigarette smoking did not alter the lack of association between oral contraceptive use and ulcerative colitis. Similarly, testing for interaction failed to demonstrate any effect modification. Analyzing for duration of current oral contraceptive use or time interval since last use failed to demonstrate a "dose-response" effect. The study was of sufficient size to detect statistical significance for oral contraceptive use for odds ratios of 2.8 and higher. In this matched case-control study of incident cases and community controls, there was no association between oral contraceptive use and ulcerative colitis incidence. To date, there is no evidence suggesting that women predisposed to the development of ulcerative colitis should be advised to avoid oral contraceptive use.

Adult↗
PubMed1991

Colonic motor response to a meal in acute colitis.

The symptoms of urgency, diarrhea, and abdominal discomfort are exaggerated after a meal in inflammatory disorders of the colon, such as ulcerative colitis. The possible motor correlates of these symptoms were investigated in a model of acute colitis in six dogs. Each dog was instrumented with seven strain gauge transducers, two on the proximal, three on the middle, and two on the distal colon. After an overnight fast, 4-hour fasted recordings were made from the normal colon and after the colon had been cleansed on the previous day with Colyte (Reed & Carnrick, Piscataway, NJ). A 1300-kcal meal was then fed, and the recordings were continued for another 8 hours. Acute colitis was then induced by the perfusion of 10 mL of 75% acetic acid and confirmed with colonoscopy and biopsy. The fasted and postprandial recordings were repeated during the next 5 days. In the control state, ingestion of the meal increased the total duration per hour of contractile activity in the early (0-2 hours) and late (2-8 hours) postprandial periods in the distal colon. In the proximal and the middle colon, a significant increase in motor activity occurred only during the late postprandial period. Similar effects were observed in the cleansed colon. By contrast, there was no significant increase in motor activity after a meal during colitis in any of the postprandial periods in the cleansed or the uncleansed colon. During colitis, there was a significant increase in the incidence of giant migrating contractions in the fasted state. The ingestion of a meal further increased the frequency of giant migrating contractions in the uncleansed colon from 0.4 +/- 0.1 to 1.3 +/- 0.5 per hour in the late postprandial period. There was no significant increase during the early postprandial period. The increase in the late postprandial frequency of giant migrating contractions was associated with an increase in defecation frequency. It is concluded that the motor response of the colon to a meal is absent in acute colitis. The entry of new ingesta into the colon during the late postprandial period stimulates enteric mechanisms to initiate an excessive number of giant migrating contractions. These giant migrating contractions may be related to increased postprandial abdominal discomfort and increased frequency of defecation.

Acute Disease↗
PubMed1993

p53 point mutations in dysplastic and cancerous ulcerative colitis lesions.

BACKGROUND: The molecular basis of colorectal dysplasia and carcinoma arising in ulcerative colitis is poorly understood. Loss of heterozygosity involving the tumor suppressor gene p53 occurs frequently in neoplastic ulcerative colitis lesions. Point mutation affecting p53 is associated with loss of heterozygosity in other cancers. Therefore, it was determined whether p53 point mutation occurs in ulcerative colitis-associated neoplasia. METHODS: Single-strand conformation polymorphism analysis, DNA sequencing, and loss of heterozygosity studies were performed on 45 patients with ulcerative colitis-associated dysplasia and carcinoma. RESULTS: Point mutations were detected in 26 lesions from 20 patients, including 18 carcinomas, 6 dysplasia-associated masses, 1 flat dysplasia, and 1 lymph node metastasis. In two cases, identical p53 mutations were observed in both carcinoma and adjacent dysplasia. Missense mutations causing amino acid substitutions as well as nonsense mutations resulting in premature stop codons were seen. Tandem mutations, in which more than 1 sequence alteration occurred on the same allele of p53, were also detected. Point mutation was accompanied by loss of the other p53 allele in 8 of 10 patients informative for both loss of heterozygosity and mutation assays. CONCLUSIONS: These findings suggest that inactivation of p53 by mutation and loss of heterozygosity is a common mechanism of malignant transformation in ulcerative colitis. They also imply that in contrast to sporadic colorectal carcinoma, ulcerative colitis-associated neoplastic progression may involve p53 inactivation at relatively early, noninvasive stages.

Chromosome Deletion↗
PubMed1994

Protective effect of epidermal growth factor in an experimental model of colitis in rats.

BACKGROUND/AIMS: The role of epidermal growth factor (EGF) in the maintenance of mucosal integrity in the lower gastrointestinal tract is unknown. The aim of this study was to determine the effect of EGF in experimental colitis. METHODS: Colitis was induced with 2,4,6-trinitrobenzenesulfonic acid/ethanol enemas. Rats were pretreated with intraperitoneal administration of recombinant human EGF (600 micrograms/kg) or vehicle 1 hour before induction of colitis and daily thereafter until killed at 8 hours, 48 hours, and 1 week. A separate group received an identical dosage and administration of EGF or vehicle for 1 week with treatment initiated 24 hours after the induction of colitis. Colonic tissue was evaluated macroscopically, histologically, and for myeloperoxidase activity. RESULTS: Pretreatment with EGF reduced microscopic erosions at 8 and 48 hours by 74% and 54%, respectively (P < 0.05). At 1 week, microscopic ulcerations and myeloperoxidase activity were reduced by 65% in the EGF-pretreated group (P < 0.05). No significant difference in macroscopic injury, histological damage, or myeloperoxidase activity was noted when EGF treatment was initiated after the induction of colitis. CONCLUSIONS: Systemic EGF administration reduces mucosal damage and inflammation in a trinitrobenzenesulfonic acid/ethanol model of colitis in rats through a mechanism involving mucosal protection.

Animals↗
PubMed1994

Molecular genetic profiles of colitis-associated neoplasms.

BACKGROUND/AIMS: A major long-term risk for patients with chronic idiopathic colitis is the development of colorectal dysplasia and adenocarcinoma. The presence or absence of specific genetic changes in these lesions will provide important insights into the relationship of colitis-associated dysplasia and the development of carcinoma. METHODS: A case-study approach was used to develop detailed molecular genetic profiles of advanced dysplasias and carcinomas from six patients with ulcerative colitis or Crohn's colitis. RESULTS: Numerous genetic alterations were identified in each of the dysplasias and carcinomas profiled. These genetic alterations involved many of the same targets found in sporadic colorectal tumors and included multiple sites of allelic deletion, microsatellite instabilities, and mutations of the K-ras, p53, and APC genes. The progression of dysplasia to carcinoma was often accompanied by an accumulation of these mutations. CONCLUSIONS: Genetic alterations are common in colitis-associated neoplasia, just as in sporadic colorectal neoplasia. This could have important implications for the evaluation and treatment of patients with colitis.

Adenocarcinoma↗
PubMed1994

Crohn's disease, ulcerative colitis, and normal intestinal lymphocytes express integrins in dissimilar patterns.

BACKGROUND/AIMS: The integrin family of adhesion molecules on intestinal lamina propria mononuclear cells (LPMNC) was studied using fluorescence-activated cell cytometry. These molecules are implicated in extravascular cell migration and are important regulators of disease. METHODS: Using fluorescence-activated cell cytometry, B- and T-cell subsets in the intestines of 10 normal patients, 11 patients with Crohn's disease, and 8 patients with ulcerative colitis were stained with monoclonal antibodies to a panel of integrins. RESULTS: Expression of alpha integrins on CD3+ T cells and CD19+ B cells was different in normal and inflammatory bowel disease LPMNC. Ulcerative colitis T cells expressed less beta 1 and alpha 4 and significantly more alpha 2 and alpha 6. There was a difference in alpha 4 and beta 1 expression between LPMNC B cells from Crohn's disease and normal intestines. Sixteen percent of CD19+ LPMNC B cells from Crohn's and 19% of ulcerative colitis LPMNC expressed alpha 2. Crohn's and ulcerative colitis CD19+ LPMNC B cells expressed more alpha 5 integrin than normal specimens. CD3+ T cells and CD19+ B cells expressed alpha 6 only in ulcerative colitis. Ulcerative colitis and Crohn's disease CD19+ LPMNC expressed less alpha 4, consistent with their reciprocal increases of alpha 5 and alpha 2. A difference in beta 7 (Peyer's patch specific) antigen was observed between inflammatory bowel disease and normal LPMNC for both CD3+ and CD19+ LPMNC. CONCLUSIONS: These findings identify the differences of lymphocyte homing capability in inflammatory bowel disease and normal intestine.

Antigens, CD↗
PubMed1994

Novel genetic association between ulcerative colitis and the anti-inflammatory cytokine interleukin-1 receptor antagonist.

BACKGROUND/AIMS: Ulcerative colitis and Crohn's disease have well-recognized familial tendencies, but the genetic basis of this clinical observation remains unknown. The cytokine interleukin-1 receptor antagonist is a potent anti-inflammatory protein that can prevent immune-mediated bowel inflammation in animals. We have previously characterized a polymorphism within the gene for this cytokine and others in the genes for the proinflammatory cytokines interleukin 1 alpha, interleukin 1 beta, and tumor necrosis factor alpha. The aim of this study was to determine whether inflammatory bowel disease was associated with particular alleles of these polymorphic cytokine genes. METHODS: The allelic frequencies of these polymorphic cytokine genes were determined in patients with ulcerative colitis (n = 113), Crohn's disease (n = 78), and healthy controls (n = 261). RESULTS: Allele 2 of interleukin-1 receptor antagonist was significantly over-represented in the ulcerative colitis patients: 35% versus 24% in controls (P = 0.007). Carriage of at least one copy of this allele gave an odds ratio of 2.0 for ulcerative colitis compared with controls. This association with allele 2 of interleukin 1 receptor antagonist was greatest in patients with total colitis and was not seen in Crohn's disease. There were no associations between UC and any of the other cytokine genes examined. CONCLUSIONS: This observation provides evidence that interleukin-1 receptor antagonist may have a role in determining the genetic susceptibility to and pathogenesis of ulcerative colitis.

Adult↗
PubMed1995

Prophylactic colectomy or surveillance for chronic ulcerative colitis? A decision analysis.

BACKGROUND & AIMS: The treatment of patients with long-standing ulcerative colitis involving the entire colon is controversial. The aim of this study was to examine the effectiveness of surveillance colonoscopy or prophylactic colectomy on colon cancer mortality in patients with chronic ulcerative colitis. METHODS: Using decision analysis, computer cohort simulation of patients with ulcerative colitis was performed to evaluate 17 strategies including no colonoscopic surveillance, surveillance at varying intervals, and prophylactic proctocolectomy with ileal pouch-anal anastomosis. The model examined which biopsy results (low-grade dysplasia, high-grade dysplasia, or cancer) should lead to proctocolectomy and ileal pouch-anal anastomosis. Published data on the incidence of cancer with ulcerative colitis, the sensitivity and specificity of colonoscopy with biopsy, the risks of colonoscopy and surgery, and the prognosis with colon cancer were used. RESULTS: For a 30-year-old patient with pancolitis for 10 years, the model suggests that prophylactic colectomy would increase life expectancy by 2-10 months compared with surveillance and by 1.1-1.4 years compared with no surveillance. Surveillance would improve life expectancy by 7 months to 1.2 years compared with no surveillance. In sensitivity analysis, results were most affected by the cumulative incidence of cancer in patients with chronic ulcerative colitis. CONCLUSIONS: Either surveillance or prophylactic colectomy should increase life expectancy in patients with ulcerative colitis.

Adult↗
PubMed1992

Oxygen radicals in ulcerative colitis.

This article reviews the pathophysiologic concept that superoxide and hydrogen peroxide, generated by activated leukocytes, together with low-molecular-weight chelate iron derived from fecal sources and from denatured hemoglobin, amplify the inflammatory response and subsequent mucosal damage in patients with active episodes of ulcerative colitis. The putative pathogenic mechanisms reviewed are as follows: (1) Dietary iron is concentrated in fecal material owing to normally limited iron absorption. (2) Mucosal bleeding, characteristic of ulcerative colitis, as well as supplemental oral iron therapy for chronic anemia, further conspire to maintain or elevate mucosal iron concentration in colitis. (3) Fenton chemistry, driven especially by leukocyte-generated superoxide and hydrogen peroxide, leads to formation of hydroxyl radicals. (4) The resultant oxidative stress leads to the extension and propagation of crypt abscesses, either through direct membrane disruption by lipid peroxidation or through generation of secondary toxic oxidants such as chloramines. (5) Chemotactic products of lipid peroxidation, including 4-hydroxynonenal, provide positive feedback to accelerate this inflammatory/oxidative process, leading to acute exacerbations of the disease. (6) Other oxidized products, such as oxidized tryptophan metabolites, created by free radical mechanisms in or near the mucosa, may act as carcinogens or tumor promotors that contribute to the exceedingly high incidence of colon carcinoma in patients suffering from chronic ulcerative colitis. In this way, self-sustaining cycles of oxidant formation may amplify flare-ups of inflammation and mucosal injury in ulcerative colitis. This concept, if proved correct by subsequent research, would provide a rationale for several novel clinical approaches to the management of ulcerative colitis, including use of SOD mimetics, iron chelators, and chain-breaking antioxidants.

Antioxidants↗
PubMed2006

Treatment with Met-RANTES decreases bacterial translocation in experimental colitis.

BACKGROUND: During colitis, epithelial function is impaired, leading to increased bacterial translocation. Recent studies have shown the important role of proinflammatory cytokines and chemokines, including RANTES (regulated on activation, normal T-cell expressed and secreted), in inflammatory bowel diseases (IBDs). In this study, we evaluated the role of Met-RANTES, an antagonist of the RANTES receptor, on the impairment of bacterial translocation in a rat model of colitis. METHODS: Rats were randomly assigned to 3 groups. Group 1 = control, group 2 = experimental colitis, and group 3 = colitis plus Met-RANTES treatment. On day 7 after colitis was induced, plasma tumor necrosis factor-alpha colon tissue myeloperoxidase and portal blood endotoxin levels were measured. Lymph node, liver, and spleen culture quantified bacterial translocation. RESULTS: Met-RANTES treatment resulted in significant decreases in colonic damage as well as bacterial translocation in experimental colitis. CONCLUSIONS: These results suggest that chemokine receptor antagonists may potentially be useful in the treatment of IBDs.

Animals↗
PubMed2005

Prevalence, detection rate and outcome of cytomegalovirus infection in ulcerative colitis patients requiring colonic resection.

OBJECTIVE: To determine the prevalence of cytomegalovirus infection in patients with steroid-refractory ulcerative colitis who required colonic resection, and to assess its possible association with the use of immunosuppressive and steroid treatment and outcome after colectomy. PATIENTS AND METHODS: The study included surgical specimens and related pre-operative endoscopic biopsy specimens of 77 consecutive ulcerative colitis patients (34 females) who underwent colectomy because of intractable steroid-refractory ulcerative colitis (55 patients), toxic megacolon (6 patients), dysplasia or cancer (7 patients) or loss of function of the colon (9 patients). Clinical features and current and past treatments were analysed. Haematoxylin and eosin and specific immunohistochemical staining for cytomegalovirus were used to detect inclusion bodies in all specimens. RESULTS: Cytomegalovirus infection was found in 15 of 55 steroid-refractory ulcerative colitis patients (27.3%) and in 2 of 22 non-refractory patients (9.1%) (p=0.123). Only six patients had positive staining for cytomegalovirus in pre-operative endoscopic biopsy specimens. Detection of cytomegalovirus inclusion in biopsy specimens was not related to the number of biopsies or to time that had elapsed since colonoscopy and index surgery. Cytomegalovirus-positive patients were more likely to be on systemic corticosteroids (p=0.03). In contrast, current use and duration of immunosuppressive treatment, number of steroid cycles since diagnosis and in the last year, as well as chronic use of steroid in the last year were not significantly related to cytomegalovirus infection. Cytomegalovirus-positive patients did not receive antiviral therapy following proctocolectomy but did not show endoscopic or histological cytomegalovirus reactivation in the ileo-anal pouch and in the remaining bowel. CONCLUSIONS: Cytomegalovirus infection is frequently found in surgical specimens of patients with steroid-refractory ulcerative colitis and is more likely in patients on corticosteroid treatment. Cytomegalovirus infection is frequently unrecognised in pre-operative biopsy specimens, thus raising concerns about the accuracy of the available diagnostic tools. Unrecognised and untreated cytomegalovirus infection does not affect the outcome of ulcerative colitis patients following proctocolectomy.

Adrenal Cortex Hormones↗
PubMed2006

Mucosal features and granulocyte-monocyte-apheresis in steroid-dependent/refractory ulcerative colitis.

BACKGROUND: Mucosa-infiltrated granulocyte neutrophils are an early characteristic of inflammation and the main histological feature of active ulcerative colitis. Mucosal healing has recently been indicated as an important tool in the evaluation of response to treatment. While several studies have stressed the efficacy of granulocyte-monocyte-apheresis in inducing clinical remission in active ulcerative colitis, few data are available on mucosal features. AIM: Aim of this study was to assess the effects of granulocyte-monocyte-apheresis on clinical and mucosal features in patients with ulcerative colitis, dependent upon or refractory to steroids. MATERIAL AND METHODS: From April 2004 to April 2005, 12 patients (5 females, 7 males, mean age 49 years, range 33-71 years), with mild-moderate ulcerative colitis (six left colitis, six pancolitis) dependent/refractory upon steroids were enrolled. Each patient was treated for a 5-week period with five cycles of granulocyte-monocyte-apheresis. Patients were evaluated at baseline and 1 week after the last apheresis by means of Global Physician Assessment, quality of life features, laboratory tests (erythrocyte sedimentation rate, CRP, full blood count, faecal calprotectine), endoscopy and histology. RESULTS: At week 6 of follow-up, complete mucosal healing was observed in 3 out of 12 patients, partial mucosal healing in 8 patients and no change in 1 patient. Clinical response was complete in 8 out of 12 patients. CONCLUSIONS: These data suggest that granulocyte-monocyte-apheresis induces an improvement both in clinical and mucosal lesions in steroid-dependent/refractory ulcerative colitis. Of note, the reduction in granulocyte infiltration and the improvement in mucosal lesions are accompanied by a reduction in faecal calprotectine.

Adult↗
PubMed2005

Differential responses of intrinsic and extrinsic innervation of smooth muscle cells in rat colitis.

Intestinal smooth muscle cells receive neural input from axons that originate within the intestine, as well as from axons of extrinsic origin. In the inflamed intestine, altered motility may arise from damage to the axon/smooth muscle cell relationship, but the extent of change is unknown. Western blotting, histology and immunocytochemistry were used in the TNBS model of colitis in the rat to evaluate intrinsic and extrinsic axon numbers, which were then correlated with circular smooth muscle cell (CSMC) number during the time course from the acute onset of colitis to apparent recovery, at Day 35 post TNBS. Total axon profiles in the circular smooth muscle layer were reduced by nearly 50% on Day 4 of colitis, to 428 +/- 82 axons/section from 757 +/- 125 in control (n = 8-14 animals). The intrinsic innervation density (axon number per CSMC) dropped sharply by Day 2 to less than 30% of control. Although CSMC number nearly tripled during colitis, innervation density was restored to control levels by Day 6 due to a coordinated three-fold increase in axon number. The subpopulation of extrinsic axons expressing tyrosine hydroxylase showed a unique pattern during colitis, with no initial decrease in axon number, followed by axonal proliferation between Days 6 and 16 post-TNBS. We conclude that loss of intrinsic axons is an early event in colitis, and although reversed by axonal proliferation, transient denervation may promote CSMC hyperplasia as seen in earlier work in vitro. Axonal proliferation of both intrinsic and extrinsic axons is identified as a major homeostatic mechanism, with distinct patterns of damage and repair suggesting a structural basis for the altered motility seen in the inflamed colon.

Animals↗
PubMed2004

Inhibition of the vanilloid receptor subtype-1 attenuates TNBS-colitis.

Primary sensory neurons are important in regard to the initiation and propagation of intestinal inflammation. The vanilloid receptor subtype-1 (VR-1) is a cation channel located on the sensory nerves that, when stimulated, release proinflammatory peptides. Previous reports have indicated that inhibition of VR-1 with capsazepine (CPZ), a VR-1 antagonist, attenuates dextran sodium sulfate (DSS) colitis in rats. DSS-induced colitis resembles ulcerative colitis with regard to its pathologic features. In this study, we examined the effect of CPZ on trinitrobenzene sulfonic acid (TNBS)-induced colitis, an experimental model of intestinal inflammation that most closely resembles the histologic and microscopic features of Crohn's disease. Colitis was induced by administering a single enema of 100 mg/kg TNBS in 50% ethanol via catheter to lightly anesthetized rats. Subsets of rats were treated with either 1 micromol/kg/ml of CPZ or CPZ-vehicle via enema for 6 days. Seven days after TNBS administration, rats were sacrificed and inflammation was assessed using a validated macroscopic damage score (MDS) and by measuring myeloperoxidase (MPO) activity. In addition, histologic examination was performed. TNBS administration resulted in reproducible chronic erosive lesions extending into the muscularis propria and extensive recruitment of neutrophils in the distal colon. MDS and MPO scores were considerably elevated in the TNBS colons when compared with the TNBS vehicle animals. TNBS rats treated with CPZ enemas exhibited a substantial reduction in MDS and MPO scores and demonstrated dramatically improved pathologic findings. Topical CPZ resulted in considerable attenuation of TNBS-induced colitis. These results support the role of VR-1 and sensory neurons with regard to intestinal inflammation.

Animals↗