vasoactive-intestinal-peptide and Crohn-Disease

The vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide (VIP/PACAP) system is considered as a paradigm for the use of a neuroendocrine-immune mediator in therapy. We review the role of VIP in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis as a murine model of Crohn's disease. VIP treatment led to the recovery of clinical factors, the amelioration of parameters related to the recruitment and traffic of cell populations, and the balance of inflammatory mediators derived from granulocytes, antigen-presenting cells and T lymphocytes including Th1, Th2 and Th17. Finally, the most recent data validate its therapeutic role through the modulation of TLR2 and 4 receptors.

Topics: Animals; Antigen-Presenting Cells; Crohn Disease; Disease Models, Animal; Granulocytes; Humans; Mice; Neuroimmunomodulation; Neurosecretory Systems; Pituitary Adenylate Cyclase-Activating Polypeptide; T-Lymphocytes; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP), first isolated from the gut, was originally considered a candidate gastrointestinal hormone. Since about 1975, however, it has become increasingly clear that it is primarily a neurotransmitter or neuromodulator and that it exerts its functions mainly by local release from nerve endings. VIP plays a hormonal role only when it is released in large amounts from a tumor, with a consequent overflow into the circulation and grossly elevated plasma concentrations of the peptide. Moderately increased VIP plasma and tissue concentrations that cause mainly local effects are found in intestinal ischemia. Crohn's disease and some other chronic inflammatory diseases of the bowel. VIP is also measured in increased amounts in the normal fetus and neonate, where it may play an important physiological role. Such an increase of VIP levels in the circulation could enhance perfusion and metabolic activity of tissues during their rapid-growth period. On the other hand, disorders with a disturbed VIP function such as achalasia and Hirschsprung's disease and possibly also asthma and cystic fibrosis seem to be characterized mainly by a derangement of smooth muscle activity and/or exocrine secretion. Considering this list of disorders where VIP has either a proven or suspected role, it is easy to imagine the significance of this peptide in pediatric pathophysiology.

Topics: Asthma; Bronchodilator Agents; Celiac Disease; Child; Child, Preschool; Crohn Disease; Cystic Fibrosis; Digestive System; Esophageal Achalasia; Hirschsprung Disease; Humans; Hypoxia; Infant; Infant, Newborn; Placenta; Vasoactive Intestinal Peptide; Vipoma

Topics: Adrenal Cortex Hormones; Adult; Cell Membrane Permeability; Child; Colitis, Ulcerative; Crohn Disease; Diarrhea; Diet; Energy Intake; Gastrointestinal Motility; Humans; Intestinal Absorption; Intestinal Mucosa; Prostaglandins; Sulfasalazine; Vasoactive Intestinal Peptide; Water-Electrolyte Imbalance; Zinc

Mast cells (MCs) and vasoactive intestinal polypeptide (VIP) have been proposed as regulators of the intestinal barrier and inflammation. Our aim was to map the distribution in inflammatory bowel disease (IBD) and murine colitis.. MCs, VIP, and VIP-receptors (VPACs) were quantified by immunofluorescence and enzyme-immunoassay (EIA) in ileal tissues (villus epithelium (VE) and adjacent VE, ie, VE next to the follicle-associated epithelium, (FAE)) from Crohn's disease (CD; n = 16) and non-IBD patients, and in colonic specimens of ulcerative colitis (UC; n = 12) and healthy controls (HCs). In addition, VIP levels were measured in plasma from HCs, non-IBD, and IBD in remission (CD n = 30; UC n = 30). Colon, ileum, and plasma from mice with dextran sulfate sodium (DSS)-induced colitis and control mice were analyzed likewise.. FAE-adjacent VE in ileum of CD possessed more MCs (P < 0.05) and MCs expressing VPAC1 (P < 0.05), but not VPAC2, compared to controls. Both adjacent and regular VE of CD had more MCs co-localizing/in close proximity to VIP (P < 0.05). In UC colon, more MCs (P < 0.0005), MCs close to VIP (P < 0.0005), and MCs expressing VPAC1 (P < 0.05) were found compared to controls. VIP levels were elevated in plasma from CD and UC compared to controls (P < 0.0005). Colon of DSS mice showed more MCs and MCs close to VIP (P < 0.05) compared to control mice. In vitro experiments revealed MCs expressing VPACs and internalized VIP after 120 minutes of VIP-stimulation.. Communication between MCs and VIP is upregulated during IBD and mice colitis. In CD patients, the epithelium next to FAE seems to be more involved than the surrounding VE, suggesting increased MC-VIP-interactions in this intestinal region.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Cell Count; Colitis, Ulcerative; Crohn Disease; Dextran Sulfate; Female; Humans; Ileum; Inflammatory Bowel Diseases; Intestinal Mucosa; Male; Mast Cells; Mice, Inbred BALB C; Middle Aged; Receptors, Vasoactive Intestinal Polypeptide, Type I; Up-Regulation; Vasoactive Intestinal Peptide; Young Adult

Neuroplastic changes in the enteric nervous system (ENS) observed during IBD might participate in physiopathological processes. Vasoactive intestinal polypeptide has been shown to be involved in intestinal inflammation and barrier functions. We aimed to investigate the modulation of VIP expression in colonic biopsies of IBD patient, the ability of soluble factors from biopsies to reproduce in vitro these modulations and identify soluble factors responsible.. VIP and cytokines mRNA expressions were assessed in colonic biopsies of healthy subjects (HS) and IBD patients from inflamed (I) and non-inflamed areas (NI). Supernatants (SUP) of biopsies were applied to primary culture of ENS and VIP and cytokines mRNA expressions were assessed. The role of cytokines in SUP induced changes in VIP expression was evaluated.. VIP mRNA expression was lower in biopsies of patients with Crohn's disease (CD) than Ulcerative Colitis (UC) but unchanged as compared to HS. VIP mRNA and protein expression were lower in primary culture of ENS incubated with SUP-CD than with SUP-UC. Furthermore, in CD but not UC, SUP-I reduced VIP expression in the ENS as compared to SUP-NI. Next, IL-6 but not IL-5, IL-10, IL-17, IFN-γ or TNF-α reduced VIP expression in the ENS. Finally, in CD, SUP-I incubated with anti-IL-6 antibody increased VIP expression as compared to SUP-I alone.. Mucosal soluble factors from IBD induce VIP neuroplastic changes in the ENS. IL-6 was identified as a putative soluble factor responsible in part for changes in VIP expression in CD.

Topics: Adolescent; Adult; Animals; Biopsy; Colon; Crohn Disease; Cytokines; Enteric Nervous System; Female; Humans; Interleukin-6; Male; Middle Aged; Neurons; Primary Cell Culture; Rats, Sprague-Dawley; RNA, Messenger; Vasoactive Intestinal Peptide; Young Adult

To investigate the modulatory effect of recombinant-expressed vasoactive intestinal peptide (VIP) analogue (rVIPa) on trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats.. Forty-eight rats were randomized into six groups: normal control group (Control), model control group (TNBS), ethanol treatment group (ETOH), and VIP treatment groups with different dosage (rVIPa. Administration with 2 nmol rVIPa prevented TNBS-induced necrosis, hyperemia, swelling, inflammation,. rVIPa ameliorates TNBS-induced colonic injury and inflammation and effectively protected the intestinal mucosal barrier function in rats. The mechanism may be related to TLR4/NF-κB-mediated signaling pathway. rVIPa could be used as a new alternative therapy for intestinal inflammatory disorders.

Topics: Animals; Colon; Crohn Disease; Diarrhea; Disease Models, Animal; Gastrointestinal Agents; Humans; Intestinal Mucosa; Male; Necrosis; NF-kappa B; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Signal Transduction; Toll-Like Receptor 4; Treatment Outcome; Trinitrobenzenesulfonic Acid; Vasoactive Intestinal Peptide

Stricture formation in Crohn's disease (CD) occurs as a result of persistent intestinal inflammatory activation, which leads to enhanced adhesion molecule expression in serosal fibroblasts (SFs). Vasoactive intestinal peptide (VIP) has anti-inflammatory and immunoregulatory properties. Treatment with VIP prevents experimental CD in animal models at the clinical and pathologic levels. The present study reports the effect of VIP on the expression of intracellular adhesion molecule-1 (ICAM-1) in IL-1beta-stimulated human colon SFs.. Primary human colon SFs were incubated with or without IL-1beta (10 ng/mL) in the presence or absence of VIP at various concentrations (0.1 to 100 nM) for designated time. Cell surface and cytosolic ICAM-1 expression were evaluated by flow cytometry and Western blot analysis, respectively. The DNA binding capacity of NF-kappaB was analyzed by electrophoretic mobility shift assay. The phosphorylation of IkappaB-alpha was examined by Western blot analysis.. VIP inhibited IL-1beta-induced expression of ICAM-1 in a dose-dependent manner. The IL-1beta-induced ICAM-1 was also inhibited by a potent inhibitor of NF-kappaB, MG132. VIP also decreased IL-1beta-induced NF-kappaB DNA binding capacity and phosphorylation of IkappaB-alpha.. VIP has an inhibitory effect on IL-1beta-induced ICAM-1 expression in SFs, which may be associated with NF-kappaB activity. This may make VIP potentially a novel therapeutic agent for preventing stricture formation in Crohn's disease.

Topics: Cells, Cultured; Colon; Crohn Disease; Fibroblasts; Gastrointestinal Agents; Humans; I-kappa B Proteins; Intercellular Adhesion Molecule-1; Interleukin-1beta; NF-kappa B; NF-KappaB Inhibitor alpha; Phosphorylation; Vasoactive Intestinal Peptide

Inflammatory bowel disease is a recurrent intestinal inflammatory disorder that in adults has been associated with changes in enteric nervous system neuropeptide expression. The aim of the present study was to determine whether similar changes were observed in paediatric Crohn's disease. The distribution of vasoactive intestinal peptide (VIP) and neuronal nitric oxide synthase (nNOS) was determined in colonic tissues from children with ileo-colonic (n=4) and colonic (n=3) Crohn's disease. The submucosal plexus of inflamed regions showed significant increase in density of VIP immunoreactive neurons (margin, 48% vs. inflamed tissue, 82% of HuC/D positive neurons). The density of submucosal plexus nNOS immunoreactive neurons was too low to be reliably quantified. Using the pan-neuronal marker HuC/D, no significant difference in numbers of HuC/D positive submucosal neurons was evident except where neurons were normalized to length of tissue (margins, 3.6+/-0.7 vs. inflamed tissue, 4.0+/-0.6 neurons/ganglia, p=0.33; margins, 2.7+/-0.4 vs. inflamed tissue, 5.7+/-1.2, neurons/mm, p=0.03). In the myenteric plexus, there was a significant increase in the percent of NOS neurons (38% vs. 82% of HuC/D positive neurons) while there was no significant difference in percent of VIP neurons (4% vs. 8%). No difference in number of HuC/D positive myenteric neurons among margin and inflamed tissues was observed (margin, 12.2+/-3.0 vs. inflamed tissue, 12.5+/-5.1 neurons/ganglia, p=0.50; margins 9.1+/-2.1 vs. inflamed tissue, 13.7+/-2.3 neurons/mm, p=0.11). These data demonstrate that inflammation is associated with a differential expression of VIP and nNOS neuronal subpopulations within the two major enteric plexi, likely due to phenotypic switch. Such changes might contribute to the pathogenesis of IBD and ongoing symptoms even in quiescent disease.

Topics: Adult; Child; Crohn Disease; ELAV Proteins; ELAV-Like Protein 3; ELAV-Like Protein 4; Female; Humans; Immunohistochemistry; Male; Muscle, Smooth; Myenteric Plexus; Nerve Fibers; Neurons; Nitric Oxide Synthase Type I; Submucous Plexus; Vasoactive Intestinal Peptide

Crohn's disease (CD) is a chronic inflammatory pathology of the intestine, characterized by diarrhea and weight loss. A healing effect of vasoactive intestinal peptide (VIP) in the murine model of CD based on 2,4,6-trinitrobencene sulfonic acid (TNBS) administration has been previously shown. The aim of this work was to analyze the expression of several mediators related to the inflammatory cascade in colitic and VIP-treated animals. With this aim, mice received either only TNBS or TNBS and VIP treatment on alternate days. cDNA microarray analysis and real-time polymerase chain reaction were performed on total mRNA from colon to study the expression of a battery of proinflammatory molecules such as the enzyme COX-2, the chemokines CX3CL1, CXCL12, CXCL13, CXCL14, CCR5, and CXCR2, and the cytokines interleukin (IL)-1beta, IL-12, IL-18, IL-10, interferon-gamma, and IL-4. TNBS administration induced the expression of all the proinflammatory mediators studied, whereas VIP treatment reduced their levels, increasing the anti-inflammatory IL-10 and the TH2 cytokine IL-4, explaining its beneficial action through inhibition of the inflammatory/TH1 response. These data describe not only the relation of several proinflammatory mediators to the development of TNBS colitis, reporting their time-course, but also show the beneficial action of VIP in this model through complete blockage of the inflammatory cascade and recovery of the colon homeostasis, providing a potential new alternative for CD therapy.

Topics: Analysis of Variance; Animals; Chemokines; Crohn Disease; Cytokines; Gastrointestinal Agents; Humans; Inflammation; Inflammation Mediators; Male; Mice; Mice, Inbred BALB C; Oligonucleotide Array Sequence Analysis; Receptors, Immunologic; Trinitrobenzenesulfonic Acid; Vasoactive Intestinal Peptide

Crohn's disease (CD) is a chronic debilitating disease of unknown etiology that is characterized by severe inflammation of the colon. Vasoactive intestinal peptide (VIP) has recently emerged as a promising candidate for treatment of inflammatory Th1-driven diseases. We studied the effect of VIP in trinitrobenzene sulfonic acid (TNBS)-induced colitis, which has clinical and molecular features in common with CD.. A 3-mg enema of TNBS was given to BALB/c mice, and VIP (1 nmol) was given either as a single dose at 12 hours or every other day. Weight loss, histopathology, and chemokine and cytokine levels in serum and colon extracts were assessed. VIP was also tested given 5 days after the onset of TNBS-induced colitis, and its effect was analyzed given a second dose of TNBS.. Treatment with VIP reduced the clinical and histopathologic severity of TNBS-induced colitis, abrogating body weight loss, diarrhea, and macroscopic and microscopic intestinal inflammation. The therapeutic effects of VIP were associated with down-regulation of both inflammatory and Th1-driven autoimmune responses, including tumor necrosis factor alpha, interleukin 1, and interleukin 6 in colon extracts and serum as well as interferon gamma by splenic and lamina propria CD4(+) T cells. VIP reduced disease severity when given after disease onset and dramatically reduced disease recurrence given a second dose of TNBS.. Our data suggest that VIP has beneficial prophylactic and therapeutic effects in TNBS-induced colitis and is a promising candidate to test for potential benefits in CD.

Topics: Animals; Colitis; Crohn Disease; Cytokines; Disease Models, Animal; Down-Regulation; Gastrointestinal Agents; Male; Mice; Mice, Inbred BALB C; Receptors, Vasoactive Intestinal Peptide; Receptors, Vasoactive Intestinal Polypeptide, Type I; Th1 Cells; Th2 Cells; Trinitrobenzenesulfonic Acid; Vasoactive Intestinal Peptide; Wasting Syndrome

Many studies have indicated changes in neuropeptides in inflammatory bowel disease (IBD), but with contradictory results. Nerve growth factor also has a potential role in the maintenance of enteric nerves and may be associated with IBD. A quantitative immunohistochemical method was used to measure area density of immunoreactive nerves in the colonic mucosa of surgical specimens. No significant differences in immunoreactivity for substance P, vasoactive intestinal polypeptide, growth associated protein 43, and the neurotrophin receptor p75 were seen in the control, Crohn's, and ulcerative colitis groups. Compared to age-matched normal colon (N = 18), there was an increase in neutrophil number in Crohn's (P < 0.05) and ulcerative colitis (P < 0.01) (both N = 9). There were positive correlations (P < 0.05) between neutrophil number and growth associated protein, between p75 and substance P immunoreactive nerves in ulcerative colitis, and between p75 and vasoactive intestinal polypeptide in Crohn's specimens. These data indicate a link between the immunologic and nervous systems in IBD.

Topics: Adult; Aged; Colitis, Ulcerative; Colon; Crohn Disease; Female; GAP-43 Protein; Humans; Immunohistochemistry; Intestinal Mucosa; Male; Middle Aged; Nerve Fibers; Nerve Growth Factors; Neuropeptides; Neutrophils; Receptor, Nerve Growth Factor; Substance P; Vasoactive Intestinal Peptide

Knowledge of the neurochemical coding of submucosal neurones in the human gut is important to assess neuronal changes under pathological conditions. We therefore investigated transmitter colocalization patterns in rectal submucosal neurones in normal tissue (n=11) and in noninflamed tissue of Crohn's disease (CD) patients (n=17). Neurone-specific enolase (NSE), choline acetyltransferase (ChAT), vasoactive intestinal polypeptide (VIP), substance P (SP), nitric oxide synthase (NOS) and calcitonin gene-related peptide (CGRP) were detected immunohistochemically in whole-mount preparations from rectal biopsies. The neuronal marker NSE revealed no differences in the number of cells per ganglion (controls 5.0; CD 5.1). Four cell populations with distinct neurochemical codes were identified. The sizes of the populations ChAT/VIP (58% vs. 55%), ChAT/SP (8% vs. 8%), and ChAT/- (22% vs. 22%) were similar in control and CD. The population VIP/- was significantly increased in CD (12% vs. 2% in controls). Unlike in controls, all NOS neurones colocalized ChAT in CD. Thickened CGRP-fibres occurred in CD. We identified neurochemically distinct populations in the human submucous plexus. The increase in the VIP/- population, extensive colocalization of ChAT and NOS and hypertrophied CGRP fibres indicated adaptive changes in the enteric nervous system in noninflamed rectum of CD patients.

Topics: Adolescent; Adult; Aged; Biopsy; Calcitonin Gene-Related Peptide; Choline O-Acetyltransferase; Colitis; Crohn Disease; Female; Humans; Immunohistochemistry; Male; Middle Aged; Neurons; Nitric Oxide Synthase; Phosphopyruvate Hydratase; Rectum; Submucous Plexus; Substance P; Vasoactive Intestinal Peptide

To study functional morphology of a total population of endocrine cells of colon mucosa, mast and enterochromaffine cells.. Light and electrone microscopy, immunohistochemical methods, morphometry were used to study endocrine and mast cells of the sigmoid colon in inflammation.. Changes of functional morphology and size of endocrine and mast cell population as well as apudocytes producing serotonin, melatonin, vasointestinal peptides were stated. Apudocyte and mass cell functional morphology, clinical symptoms and mucosal structural changes correlated. Specificity of some parameters in Chron's disease is shown.. The results may provide additional criteria in diagnosis of different variants of chronic colitis.

Topics: Adolescent; Adult; APUD Cells; Biopsy; Colitis; Crohn Disease; Humans; Intestinal Mucosa; Mast Cells; Melatonin; Middle Aged; Prognosis; Serotonin; Sigmoid Diseases; Vasoactive Intestinal Peptide

There have been conflicting results regarding the effect of Crohn's disease on the neurochemical composition of the enteric nervous system.. To examine the effect of Crohn's disease on the neurochemical composition of enteric nerve fibres and cell bodies using whole mount preparations of human ileum.. Whole wall ileum from seven normal subjects and nine patients with Crohn's disease was used to investigate the neurochemical composition of neurones and nerve fibres in the myenteric plexus, circular muscle, and serosa layer of ileum using immunohistochemical techniques.. Increased tyrosine hydroxylase, 5-hydroxytryptamine, and neuropeptide Y immunoreactivity was exclusively seen in the myenteric plexus. There was increased neurofilament immunoreactivity in the myenteric plexus and nerve fibres of the circular muscle layer, and thick bundles of immunoreactive nerve fibres in the serosa layer. Increased vasoactive intestinal polypeptide, nitric oxide synthase, and pituitary adenylate cyclase activating peptide immunoreactivity was seen in the myenteric plexus and nerve fibres of the circular muscle layer, and aggregates of inflammatory cells in the serosa layer of the afflicted segment of Crohn's ileum. In addition, there was a chaotic display of nerve fibres containing some of the neuroactive substances with a high frequency of enlarged varicosities in the myenteric ganglia and/or nerve fibres of the circular muscle layer of Crohn's ileum.. Results show quantitative as well as qualitative changes in the neurochemical composition of enteric nerve fibres and nerve cell bodies of Crohn's ileum. These changes and the presence of nitric oxide synthase and peptides immunoreactive inflammatory cells in the serosa layer suggest that nerve-immune interactions may have a significant role in the process of the inflammatory changes seen in Crohn's ileitis.

Topics: Adult; Aged; Crohn Disease; Enteric Nervous System; Fluorescent Antibody Technique, Indirect; Humans; Ileitis; Ileum; Image Processing, Computer-Assisted; Middle Aged; Neuropeptide Y; Neuropeptides; Neurotransmitter Agents; Nitric Oxide Synthase; Pituitary Adenylate Cyclase-Activating Polypeptide; Serotonin; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

To investigate the effects of PACAP-27 on electrolyte transport across the isolated human intestinal mucosa, changes in short-circuit current (Isc) were measured in Ussing chamber experiments. Serosally added PACAP-27 increased Isc in a concentration-dependent manner, eliciting a similar maximal effect in both the jejunal and the colonic mucosa. Bumetanide inhibited Isc responses, indicating stimulation of Cl- secretion. The potency and efficacy of PACAP-27 were comparable to those of VIP, suggesting that both peptides activate intestinal secretion by way of a common receptor located in the basolateral membrane of the intestinal epithelium.

Topics: Colon; Crohn Disease; Dose-Response Relationship, Drug; Electrolytes; Gastrointestinal Hormones; Humans; In Vitro Techniques; Intestinal Mucosa; Jejunum; Membrane Potentials; Natriuretic Peptides; Neuropeptides; Neurotransmitter Agents; Peptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Tetrodotoxin; Vasoactive Intestinal Peptide

The distribution abnormality of vasoactive intestinal polypeptide-containing nerves (VIP-nerves) and substance P-containing nerves (SP-nerves) was immunohistochemically investigated in the colonic mucosa with inflammatory bowel disease (IBD) in relation to colonic glands and blood vessels in the lamina propria. In active ulcerative colitis (UC), VIP- and SP-nerves decreased in severe inflammatory lesions. VIP-nerves were almost absent particularly around crypt abscesses. Even in resolving and quiescent UC, VIP-nerves still decreased, depending on the decrease of glands and blood vessels. On the other hand, both nerves increased in some hypervascular lesions. In the uninvolved mucosa of UC, they did not change their distribution. In Crohn's disease, the distribution abnormality of both nerves resembled that of UC. These results suggest that the changes in VIP- and SP-nerve distributions in the mucosa with IBD are subsequent to mucosal inflammation and damage. However, these peptides are known to be immunoregulators, and their distribution abnormalities may induce the disorder of immunoregulation in the IBD mucosa and cause the mucosal damage and/or chronicity.

Topics: Adolescent; Adult; Aged; Colitis, Ulcerative; Colon; Crohn Disease; Female; Humans; Immunohistochemistry; Intestinal Mucosa; Male; Middle Aged; Nerve Fibers; Neuropeptides; Substance P; Vasoactive Intestinal Peptide

Neuropeptides form a part of the brain-gut axis which may regulate gastrointestinal functions, including immune regulation. Various changes in the neuropeptides--most important, vasoactive intestinal peptide and substances P (VIP and SP)--have been described in inflammatory bowel disease. We employed a sensitive immunoperoxidase (avidin-biotin-peroxidase complex) technique, using anti-VIP and anti-SP antibodies to localize and compare the distribution of VIP and SP in the colon. Colon specimens from 19 normal subjects, eight patients with ulcerative colitis (UC), and eight with Crohn's disease (CD) were used. In the normal colon, VIP and SP immunoreactivity (IR) were localized in the muscularis mucosa, circular muscles, walls of blood vessels, nerve fibers, and some distinct cells, probably enterochromaffin cells. SP-IR was also present in the epithelial cells, mainly along the basolateral domain. VIP-IR was considerably diminished at all locations in patients with UC and CD. However, the SP-IR was increased in UC in the colonic epithelial cells along the basolateral areas. The SP-IR was intense in patients with CD, in the epithelium, the granulomas, cells lining the mucosal fissure, and in the muscle layers. In contrast to normals, SP-IR in patients with CD was observed both in the longitudinal and circular muscles. We conclude that VIP-IR and SP-IR are distributed widely in the mucosa, submucosa, and in the circular muscle in normal colon. VIP-IR is decreased in UC and CD, whereas SP-IR is increased in both, but more so in CD.

Topics: Colitis, Ulcerative; Colon; Crohn Disease; Humans; Immunoenzyme Techniques; Inflammatory Bowel Diseases; Reference Values; Substance P; Vasoactive Intestinal Peptide

To determine whether decreased tissue vasoactive intestinal polypeptide levels might affect inhibitory neural input, fresh colonic specimens were obtained from patients with Crohn's colitis (n = 7) and normal subjects (n = 13). Immunoreactive vasoactive intestinal polypeptide levels were measured in the muscularis externa by radioimmunoassay and localized in tissue sections by immunostaining. Circular muscle strips were maintained in an organ bath; inhibitory junction potentials evoked by short- and long-duration field stimulation and resting membrane potentials were recorded using intracellular impalements. In Crohn's colitis, vasoactive intestinal polypeptide levels displayed a bimodal distribution in which 3 specimens had vasoactive intestinal polypeptide levels greater than or equal to 4 SE lower than the mean in normal specimens. In 3 specimens from Crohn's colitis with decreased vasoactive intestinal polypeptide levels, immunoreactive material was absent from the circular muscle layer and the myenteric plexus. Mean resting membrane potentials, mean amplitude of inhibitory junction potentials evoked by short-duration stimulation, and mean amplitude of initial inhibitory junction potentials evoked by long-duration stimulation were not different between the two groups. However, the mean amplitude of the 60th inhibitory junction potential during prolonged stimulation was decreased (p less than 0.01) in Crohn's colitis (6 mV) compared with normal specimens (11 mV). These results show that diminished neural input to circular muscle in Crohn's colitis was associated with decreased extractable vasoactive intestinal polypeptide levels and decreased staining of nerve fibers containing vasoactive intestinal polypeptide.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Crohn Disease; Evoked Potentials; Female; Humans; Immunohistochemistry; Male; Membrane Potentials; Middle Aged; Muscle, Smooth; Myenteric Plexus; Nerve Fibers; Peptide PHI; Vasoactive Intestinal Peptide

The study was undertaken to examine regional differences in the concentrations of five regulatory peptides in the human colonic mucosa. Biopsies were obtained during routine colonoscopy from 33 patients whose colonic mucosa was macroscopically and histologically normal. Regulatory peptides were extracted, and measured by specific radioimmunoassays. Concentrations of three peptides that are present predominantly in endocrine cells within colonic mucosa increased significantly towards the rectum: Mean concentrations of peptide YY, enteroglucagon, and somatostatin were about three times greater in the rectum than in the cecum. However, concentrations of two peptides that are present in mucosal nerve fibers diminished significantly towards the rectum: Mean rectal concentrations of vasoactive intestinal peptide and peptide histidine methionine were both about 0.6 of mean cecal concentrations. Concentrations of all five peptides were lower in biopsies taken from colonic polyps than in normal colonic mucosa. Regional differences in colonic mucosal concentrations of regulatory peptides probably reflect differences in the physiological functions of different parts of the colon.

Topics: Adolescent; Adult; Aged; Cecum; Colitis, Ulcerative; Colon; Colonic Polyps; Crohn Disease; Female; Gastrointestinal Hormones; Glucagon-Like Peptides; Humans; Intestinal Mucosa; Male; Middle Aged; Peptide PHI; Peptide YY; Peptides; Radioimmunoassay; Rectum; Somatostatin; Vasoactive Intestinal Peptide

Circulating levels of vasoactive intestinal peptide (VIP) in plasma were measured in gauging activity in inflammatory bowel disease (IBD). One hundred-fifteen adult IBD patients were studied cross-sectionally and prospectively, 48 with ulcerative colitis (UC) and 67 with Crohn's disease (CD). Sequential samples of plasma were assayed for VIP by specific radioimmunoassay. Sixty males and 55 females, ranging in age from 22 to 76 years were studied over six months. The results revealed a strong, positive association between VIP levels and clinical activity, both at baseline (r = 0.38, P less than 0.001) and follow-up (r = .41, P less than 0.001). The ability of the VIP immunoassay to gauge clinical activity was also evaluated where VIP concentrations above 30 pg/ml were defined as abnormal. At baseline, sensitivity (specificity) was found to be 81% (55%). The predictive value of a positive (negative) test was 57% (80%). These estimates did not differ at follow-up. Examination of paired plasma samples from intermittently active patients revealed nearly twofold increases (P less than 0.05) in VIP concentration during active periods of disease. The data suggest that plasma VIP levels may be a valuable laboratory parameter in gauging activity in inflammatory bowel disease.

Topics: Adult; Colitis, Ulcerative; Crohn Disease; Female; Follow-Up Studies; Humans; Immunoassay; Male; Sex Factors; Vasoactive Intestinal Peptide

Topics: Colitis; Crohn Disease; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Neurotensin; Rectum; Somatostatin; Vasoactive Intestinal Peptide

The sequence for peptide histidine-methionine is present within the same preprohormone as vasoactive intestinal polypeptide. Since our previous study using radioimmunoassay had demonstrated significantly decreased colonic concentrations of vasoactive intestinal polypeptide in ulcerative colitis and Crohn's colitis compared to normal colon, we determined the distribution and quantitation of peptide histidine-methionine. Fresh surgical specimens were dissected into mucosal-submucosal and muscularis externa layers prior to acid extraction and specific radioimmunoassay. One immunoreactive species that appeared to coelute with peptide histidine-methionine was separated by reverse-phase high-performance liquid chromatography. Mucosal-submucosal concentrations of peptide histidine-methionine were significantly decreased in ulcerative colitis and Crohn's colitis, compared to those in normal colon. In normal ileum and colon, linear correlation analysis showed no relationship between patient age and tissue concentrations of peptide histidine-methionine. However, a parallel decrease in molar concentrations of peptide histidine-methionine and vasoactive intestinal polypeptide in ulcerative colitis and Crohn's colitis was demonstrated by linear correlation analysis. These results are consistent with the hypothesis that peptide histidine-methionine and vasoactive intestinal polypeptide are colocalized within the same neural structures that have been altered in the idiopathic inflammatory bowel diseases.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Chromatography, High Pressure Liquid; Colitis, Ulcerative; Colon; Crohn Disease; Humans; Ileum; Intestinal Mucosa; Middle Aged; Peptide PHI; Radioimmunoassay; Vasoactive Intestinal Peptide

To study hyperplasia of peptidergic nerves purported to be diagnostic of Crohn's disease, we determined the distribution and concentrations of gut neuropeptides in specimens of normal intestine, ulcerative colitis, and Crohn's disease. Tissue specimens obtained at surgery were dissected into the mucosal-submucosal and muscularis externa layers, and immunoreactive gut neuropeptides were acid-extracted for measurement by radioimmunoassay. The immunoreactive species were characterized by column chromatography. Mucosal-submucosal layer concentrations of vasoactive intestinal peptide were significantly decreased in Crohn's colitis and ulcerative colitis, while mucosal-submucosal layer concentrations of substance P were significantly increased in left-sided ulcerative colitis. Muscularis externa layer concentrations of vasoactive intestinal peptide and met5-enkephalin were decreased in left-sided Crohn's colitis. These neuropeptide concentration abnormalities did not clearly differentiate between Crohn's colitis and ulcerative colitis, and no increase in concentration of a neuropeptide diagnostic of Crohn's disease was identified.

Topics: Adult; Aged; Bombesin; Chromatography; Colitis, Ulcerative; Crohn Disease; Enkephalin, Methionine; Histocytochemistry; Humans; Intestinal Mucosa; Middle Aged; Neuropeptides; Radioimmunoassay; Substance P; Vasoactive Intestinal Peptide

The number of peptide hormones which have been localized in the gut and in neurons of the central and peripheral nervous system has increased considerably. As there is almost no information about their importance in children with gastrointestinal diseases, we developed highly sensitive radioimmunoassays and measured postprandial serum/plasma levels of gastrin, secretin, vasoactive intestinal polypeptide (VIP) and motilin in 112 healthy children (N), 28 patients with cystic fibrosis (CF) and 17 children with Crohn's disease (CD). Gastrin values were not pathologic in children with CF nor those with Crohn's disease (N = 56.2 +/- 29.6 pg/ml; CF = 57.0 +/- 34.2 pg/ml; CD = 43.6 +/- 26.6 pg/ml). A significant age dependency was established for secretin and VIP. These peptides were elevated in CF-patients. In children with Crohn's disease only Secretin was increased. Motilin was elevated in all patients: N = 78.0 (49.1-124.0) pg/ml; CF = 148.0 (70.8-309) pg/ml; CD = 153.0 (87.6-266).

Topics: Adolescent; Adult; Child; Child, Preschool; Crohn Disease; Cystic Fibrosis; Gastrins; Humans; Infant; Motilin; Radioimmunoassay; Secretin; Vasoactive Intestinal Peptide

Vasoactive intestinal polypeptide (VIP)-containing nerves and VIP content of endoscopic rectal biopsies from 47 patients with inflammatory bowel disease and 17 normal controls were examined by immunocytochemistry and radioimmunoassay. Immunocytochemistry revealed a consistent increase in, and abnormal appearance of, VIP nerves in patients with Crohn's disease not only those with rectal involvement but also patients with no histological evidence of rectal disease. Normal control biopsies contained 1.64 +/- 0.39 pmol VIP/mg protein as compared with 3.43 +/- 1.24 pmol VIP/mg protein in tissue from patients with rectal Crohn's disease and 5.37 +/- 1.23 pmol VIP/mg protein in those with Crohn's disease without rectal involvement. Ten of the 17 biopsies examined from ulcerative colitics showed a normal pattern of VIP innervation. Examination of the conventional histology of these biopsies showed that only areas with obvious active proctitis had increased VIP nerves and, unlike the appearance in Crohn's disease, these nerves had a normal morphology. The VIP content of these biopsies was similar to that of the controls; 1.34 +/- 0.37 pmol/mg protein.

Topics: Adolescent; Adult; Aged; Colitis, Ulcerative; Crohn Disease; Fluorescent Antibody Technique; Humans; Intestinal Mucosa; Middle Aged; Proctitis; Radioimmunoassay; Rectum; Vasoactive Intestinal Peptide

Neurones containing VIP, substance P, or enkephalin were studied by immunocytochemistry in intestinal specimens from 27 patients with Crohn's disease. Also several endocrine cell systems in the gut were examined. The results were compared with those from a control group of 26 patients. The relative frequency of various endocrine cells did not differ overtly from that in controls. Vasoactive intestinal polypeptide and substance P nerve fibres were distributed in all layers of the gut wall, including the submucosal and myenteric plexuses, whereas enkephalin fibres were restricted to the smooth muscle layer and the myenteric plexus. The distribution and frequency of the peptide-containing nerve fibres were the same in Crohn's disease patients as in control patients. A proportion of these nerve fibres, however, were notably coarse in the Crohn's disease patients. This was particularly apparent in the afflicted parts of the intestine although it was noted also in non-afflicted parts. The concentration of VIP and substance P (expressed as pmol/g wet weight) did not, however, exceed that of the control group.

Topics: Adolescent; Adult; Aged; Cell Count; Colon; Crohn Disease; Enkephalins; Female; Fluorescent Antibody Technique; Gastrointestinal Hormones; Humans; Ileum; Intestinal Mucosa; Male; Middle Aged; Muscle, Smooth; Myenteric Plexus; Neurons; Substance P; Vasoactive Intestinal Peptide

We have studied fasting levels and the response to a standard test breakfast of blood glucose and several gut hormones in 24 patients with ulcerative colitis, in 14 patients with Crohn's disease, and in 14 healthy control subjects. Patients with ulcerative colitis had significantly elevated fasting human pancreatic polypeptide (HPP) concentrations, and both basal and postprandial levels of gastrin, gastric inhibitory polypeptide (GIP), and motilin were greater than normal. In contrast, patients with Crohn's disease had normal gastrin levels but had increased fasting and postprandial levels of GIP and motilin and, in addition, of enteroglucagon, compared with controls. These patients also had greater than normal HPP concentrations 30 min after the breakfast. Normal levels of insulin, pancreatic glucagon, neurotensin, and vasoactive intestinal polypeptide were found in both groups of patients. Much remains to be known about the pathophysiology of these two debilitating diseases, and the abnormal release of gut hormones may be of importance.

Topics: Adolescent; Adult; Aged; Blood Glucose; Colitis, Ulcerative; Crohn Disease; Female; Gastric Inhibitory Polypeptide; Gastrins; Gastrointestinal Hormones; Glucagon-Like Peptides; Humans; Insulin; Male; Middle Aged; Motilin; Neurotensin; Pancreatic Polypeptide; Vasoactive Intestinal Peptide

Topics: Animals; Crohn Disease; Gastrointestinal Diseases; Gastrointestinal Hormones; Hepatic Encephalopathy; Humans; Hypertension; Rats; Receptors, Cell Surface; Vasoactive Intestinal Peptide

The possible involvement of nerves containing vasoactive intestinal polypeptide in Crohn's disease was investigated by immunocytochemistry and radioimmunoassay of specimens from 17 patients with well-defined clinical and histologic features of the disease. The characteristic pattern of slender fibers, evenly distributed across the gut wall, was seen in specimens taken from controls, which consisted of (a) specimens from uninvolved areas of gut from carcinoma resection (n = 17) and (b) jejunoileal specimens obtained during bypass operation for obesity (n = 8) as well as in four of the six specimens from patients with ulcerative colitis. In contrast, this characteristic pattern was lost in all 17 patients with Crohn's disease, the pattern being replaced by thickened and more intensely immunostained fibers. These changes were consistently found in the mucosa and submucosa, and in 13 of the Crohn's disease cases, the abnormal pattern was totally transmural, involving both the myenteric and submucous plexus as well as the muscle layers. There was a > 200% increase in VIP content, as determined by radioimmunoassay, in Crohn's disease (294 +/- 29 pmol/g wet wt, mean +/- SEM) in comparison with (a) ulcerative colitis (93 +/- 5 pmol/g [P < 0.001]), and (b) controls consisting of carcinoma resection (108 +/- 39) and bypassed gut from obese patients (86 +/- 27 [P < 0.001]). At least part of the previously documented autonomic nerve changes in Crohn's disease are, thus, due to an increase in vasoactive intestinal polypeptide innervation.

Topics: Adolescent; Adult; Aged; Autonomic Nervous System; Colitis, Ulcerative; Colon; Crohn Disease; Gastrointestinal Hormones; Humans; Ileum; Immune Sera; Intestinal Mucosa; Middle Aged; Radioimmunoassay; Vasoactive Intestinal Peptide

Topics: APUD Cells; Autonomic Nervous System; Bombesin; Brain; Chagas Disease; Cholecystokinin; Crohn Disease; Endocrine Glands; Endorphins; Gastrointestinal Hormones; Humans; Immunochemistry; Megacolon; Neurotensin; Neurotransmitter Agents; Peptides; Somatostatin; Substance P; Vasoactive Intestinal Peptide