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The neuronal and non-neuronal substance P, VIP and cholinergic systems in the colon in ulcerative colitis
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease. Neuropeptides, especially vasoactive intestinal peptide (VIP) and substance P (SP), have long been considered to play key roles in UC. Among other effects, these neuropeptides have trophic and growth-modulating as well as wound-healing effects. Furthermore, whilst VIP has anti-inflammatory properties, SP has pro-inflammatory effects. It is generally assumed that the main source of SP and VIP in the intestine is the tissue innervation. It is not known whether or not they are produced in the epithelial layer. The details concerning the expressions of their receptors in UC are also, to a great extent, unclear. Apart from the occurrence of peptidergic systems in the intestine, there are also neuronal as well as non-neuronal cholinergic systems. The pattern concerning the latter is unknown with respect to UC.

The studies in this thesis aimed to investigate the expression of SP and VIP and their major receptors (NK-1R and VPAC1) in UC colon, compared to non-UC colon. The main emphasis was devoted to the epithelium. A second aim was to examine for levels of these neuropeptides in blood plasma in UC. Another aim was to examine for the non-neuronal cholinergic system in UC, thus, to investigate whether there is acetylcholine production outside nerves in the UC colon. Methods used in the thesis were immunohistochemistry, in situ hybridization, enzyme immunosorbent assay, and in vitro receptor autoradiography.

For the first time, mRNA for VIP and SP has here been found in the colonic epithelium. That was especially noted in UC mucosa showing a rather normal morphology, and in non-UC mucosa. Marked derangement of the mucosa was found to lead to a distinct decrease in VIP binding, and also a decrease in the expression level of VIP receptor VPAC1 in the epithelium. In general, there was an upregulation of the SP receptor NK-1R in the epithelium when the mucosa was deranged. The plasma levels of SP and VIP were higher for UC patients compared to healthy controls. There were marked correlations between the levels of the peptides in plasma, their levels in the mucosa and the degree of mucosal derangement/inflammation. A pronounced nonneuronal cholinergic system was found in both UC and non-UC colon. Certain changes occurred in this system in response to inflammation/derangement in UC. The present study shows unexpectedly that expressions for VIP and SP are not only related to the nerve structures and the inflammatory cells. The downregulation of VPAC1 expression, and the tendencies of upregulation of NK-1R expression levels when there is marked tissue derangement, may be a drawback for the intestinal function. The study also shows that there is a marked release of neuropeptides to the bloodstream in parallel with a marked derangement of the mucosa in UC. The cholinergic effects in the UC colon appear not only to be associated with nerverelated effects, but also effects of acetylcholine produced in local non-neuronal cells. The thesis shows that local productions for not only acetylcholine, but also SP and VIP, occur to a larger extent than previously considered.

Place, publisher, year, edition, pages
Umeå: Institutionen för integrativ medicinsk biologi , 2009. , 62 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1248
Keyword [en]
ulcerative colitis, neuropeptides, substance P, VIP, non-neuronal cholinergic system
National Category
Cell and Molecular Biology Surgery
Research subject
Human Anatomy
Identifiers
URN: urn:nbn:se:umu:diva-19946ISBN: 978-91-7264-731-2 (print)OAI: oai:DiVA.org:umu-19946DiVA: diva2:207806
Public defence
2009-04-03, BiA 201, Biologihuset, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2009-03-13 Created: 2009-03-12 Last updated: 2010-04-15Bibliographically approved
List of papers
1. Substance P and the neurokinin-1 receptor in relation to eosinophilia in ulcerative colitis
Open this publication in new window or tab >>Substance P and the neurokinin-1 receptor in relation to eosinophilia in ulcerative colitis
2005 (English)In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 26, no 5, 799-814 p.Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
adult, aged, colitis, ulcerative/metabolism/pathology, colon/pathology, eosinophilia/pathology, female, humans, intestinal mucosa/immunology, male, middle aged, muscle, smooth/immunology, myenteric plexus/immunology, nerve fibers/immunology, receptors, neurokinin-1/analysis/metabolism, substance P/analysis/metabolism
Identifiers
urn:nbn:se:umu:diva-6041 (URN)10.1016/j.peptides.2004.12.018 (DOI)15808910 (PubMedID)
Available from: 2007-12-05 Created: 2007-12-05 Last updated: 2017-12-14Bibliographically approved
2. Decrease in binding for the neuropeptide VIP in response to marked inflammation of the mucosa in ulcerative colitis
Open this publication in new window or tab >>Decrease in binding for the neuropeptide VIP in response to marked inflammation of the mucosa in ulcerative colitis
2007 (English)In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1107, 280-289 p.Article in journal (Other academic) Published
Abstract [en]

The neuropeptide vasoactive intestinal peptide (VIP) is involved in the neuroimmunomodulation of the intestine. In the present study, specimens from the sigmoid colon of ulcerative colitis (UC) and non-UC patients were examined for immunohistochemistry and in vitro receptor autoradiography. Marked occurrence of VIP binding was observed in the mucosa. However, there were very low levels of binding in areas showing pronounced inflammation/derangement. The study shows that marked derangement of the mucosa leads to a distinct decrease in VIP binding. Thus, it is possible that a decrease in trophic and anti-inflammatory VIP effects occurs in areas exhibiting a very marked inflammation.

Keyword
adult, aged, aged; 80 and over, autoradiography, biological markers, colitis, ulcerative/metabolism/pathology, female, gastric mucosa/metabolism/pathology, humans, immunohistochemistry, inflammation/metabolism/pathology, intestinal mucosa/metabolism/pathology, male, middle aged, receptors, vasoactive intestinal peptide/metabolism, vasoactive intestinal peptide/metabolism
Identifiers
urn:nbn:se:umu:diva-8144 (URN)10.1196/annals.1381.030 (DOI)17804556 (PubMedID)
Available from: 2008-01-15 Created: 2008-01-15 Last updated: 2017-12-14Bibliographically approved
3. Presence of mRNA for VIP and Substance P and presence of VPAC1 and NK-1 receptor expressions in the colonic epithelium of man: changed pattern in ulcerative colitis
Open this publication in new window or tab >>Presence of mRNA for VIP and Substance P and presence of VPAC1 and NK-1 receptor expressions in the colonic epithelium of man: changed pattern in ulcerative colitis
(English)Manuscript (Other academic)
Abstract [en]

 

The neuropeptides vasoactive intestinal peptide (VIP) and substance P (SP) are considered to be important in ulcerative colitis (UC). It is generally assumed that the main source of VIP and SP in the intestine is the innervation. There is no information concerning whether or not they are produced by cells in the epithelial layer. Concerning UC, there is also a lack of information concerning the VIP-receptor VPAC1 in the epithelium. In the present study, UC and non-UC colon was examined concerning expressions of VIP, SP, VPAC1 and the SP-preferred receptor, neurokinin-1 (NK-1R). Both immunohistochemistry and in situ hybridization were applied. mRNA expression for both VIP and SP were observed in the epithelium. The mRNA reactions were seen in normal and little/moderately affected mucosa. There were very marked VPAC1 immunoreactions in the epithelium, in non-UC mucosa and in little affected UC mucosa. A decrease in VPAC1 immunoreactions was noted in the epithelium in markedly affected UC mucosa. Existence of VIP immunoreaction, VIP mRNA, VPAC1 immunoreaction, SP mRNA, NK-1R immunoreaction and Substance P receptor (TACR1) mRNA was shown for cells in lamina propria and submucosa. The present study shows unexpectedly that mRNA for both VIP and SP are not only expressed in neuronal perikarya and lamina propria and submucosal cells but also in the colonic epithelium, and that marked changes in VPAC1 receptor expressions occur for this layer in severe UC. It is tentative to speculate that autocrine/paracrine VIP and SP effects may occur within the epithelium. The decrease in VPAC1 receptor reactions seen in severely UC affected mucosa may be a drawback for the intestinal function.

 

Keyword
colitis, colonic epithelium, SP, VIP, VPAC1, NK-1 receptor
National Category
Cell and Molecular Biology
Research subject
Human Anatomy
Identifiers
urn:nbn:se:umu:diva-19945 (URN)
Available from: 2009-03-13 Created: 2009-03-12 Last updated: 2010-06-24Bibliographically approved
4. New aspects concerning ulcerative colitis and colonic carcinoma: analysis of levels of neuropeptides, neurotrophins, and TNFalpha/TNF receptor in plasma and mucosa in parallel with histological evaluation of the intestine
Open this publication in new window or tab >>New aspects concerning ulcerative colitis and colonic carcinoma: analysis of levels of neuropeptides, neurotrophins, and TNFalpha/TNF receptor in plasma and mucosa in parallel with histological evaluation of the intestine
2008 (English)In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 14, no 10, 1331-1340 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The levels of neuropeptides, neurotrophins, and TNFalpha (TNFalpha)/TNF receptor in plasma and mucosa for patients with ulcerative colitis (UC) and colonic carcinoma, and concerning plasma also for healthy controls, were examined. Moreover, the relationships between the different substances and the influence of mucosal derangement on the levels were analyzed.

METHODS: The levels of VIP, SP, CGRP, BDNF, NGF, and TNFalpha/TNF receptor 1 were measured using ELISA/EIA.

RESULTS: Patients with UC demonstrated the highest levels of all analyzed substances in plasma, with the exception of BDNF. However, there were differences within the UC group, patients treated with corticosteroids, and/or nonsteroid antiinflammatory/immunosuppressive treatment having higher plasma levels than those not given these treatments. Patients with colonic carcinoma showed higher SP and TNF receptor 1 levels in plasma compared to healthy controls. Concerning mucosa, the levels of almost all analyzed substances were elevated for patients with UC compared to noncancerous mucosa of colonic carcinoma patients. There were correlations between many of the substances in both plasma and mucosa, especially concerning the 3 neuropeptides examined. There were also marked associations with mucosa derangement.

CONCLUSIONS: Via analysis of correlations for the respective patients and via comparisons between the different patient groups, new and original information was obtained. Interestingly, the degree of mucosal affection was markedly correlated with tissue levels of the substances and the treatments were found to be of importance concerning plasma but not tissue levels of these. Combined plasma analysis of neuropeptides, neurotrophins, and TNF receptor 1 may help to distinguish UC and colonic carcinoma patients.

Identifiers
urn:nbn:se:umu:diva-19265 (URN)10.1002/ibd.20487 (DOI)18452198 (PubMedID)
Available from: 2009-03-05 Created: 2009-03-05 Last updated: 2017-12-13Bibliographically approved
5. Presence of a marked nonneuronal cholinergic system in human colon: study of normal colon and colon in ulcerative colitis
Open this publication in new window or tab >>Presence of a marked nonneuronal cholinergic system in human colon: study of normal colon and colon in ulcerative colitis
2007 (English)In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 13, no 11, 1347-1356 p.Article in journal (Other academic) Published
Abstract [en]

BACKGROUND: The body has not only a neuronal but also a nonneuronal cholinergic system. Both systems are likely to be very important, particularly in inflammatory conditions. The patterns and importance of the nonneuronal cholinergic system in patients with ulcerative colitis (UC) are largely unknown.

METHODS: The colons of UC and non-UC patients were examined for expression patterns of choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), and the muscarinic receptor of the M(2) subtype.

RESULTS: ChAT and VAChT immunoreactions and mRNA reactions for ChAT were detected in epithelial and endocrine cells, in cells in the lamina propria, and in blood vessel walls. Furthermore, a marked M(2) immunoreaction was noted for epithelium, blood vessel walls, and smooth musculature. ChAT and VAChT immunoreactions were significantly higher in endocrine and epithelial cells, respectively, in non-UC mucosa than in UC mucosa. On the other hand, there was a tendency toward higher M(2) levels in epithelium of UC patients.

CONCLUSIONS: There is a pronounced nonneuronal cholinergic system in the colon, which has previously been ignored when discussing cholinergic influences in UC. Furthermore, it is evident that certain changes in the nonneuronal cholinergic system occur in response to inflammation/derangement in UC. Cholinergic effects in the colon can be considered to be related not only to nerve-related effects but also to effects of acetylcholine from nonneuronal local cells. Thus, the recently discussed phenomenon of a "cholinergic antiinflammatory pathway" in the intestine may have a pronounced nonneuronal component.

Keyword
adult, case-control studies, choline O-acetyltransferase/analysis, colitis, ulcerative/metabolism/pathology, colon/metabolism/pathology, female, humans, inflammation/metabolism, male, middle aged, receptor, muscarinic M2/analysis, tissue distribution, vesicular acetylcholine transport proteins/analysis
Identifiers
urn:nbn:se:umu:diva-8145 (URN)10.1002/ibd.20224 (DOI)17663429 (PubMedID)
Available from: 2008-01-15 Created: 2008-01-15 Last updated: 2017-12-14Bibliographically approved

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