Dataset Information

Gut mucosal granulocyte activation precedes nitric oxide production: studies in coeliac patients challenged with gluten and corn.

ABSTRACT:

Background and aims

To elucidate the dynamics of nitric oxide (NO) production induced by rectal gluten challenge and the relation between NO production and mucosal granulocyte activation.

Subjects and methods

Release of rectal NO was measured in 13 patients with coeliac disease and in 18 controls before and after rectal wheat gluten challenge. Rectal gas was collected with a rectal balloon using a newly developed instrument/technique, the "mucosal patch technique". The instrument allows simultaneous measurements of concentrations of granulocyte mediators in the rectal mucosa. We measured myeloperoxidase (MPO), eosinophil cationic protein (ECP), and histamine. For comparison, we made similar measurements after corn (maize) gluten challenge.

Results

In all coeliac patients rectal NO concentration increased after gluten challenge and reached a peak after 15 hours (mean 9464 (SEM 2393) parts per billion (ppb); range 250-24982). The maximum MPO and ECP increase occurred five hours after challenge. A correlation was found between mucosal MPO and NO production at 15 hours. Six of the patients showed an increase in NO production 15 hours after rectal corn gluten challenge but this was much smaller than after gluten challenge. No increases were seen in the control group after either challenge.

Conclusion

Mucosal activation of neutrophils and eosinophils precedes pronounced enhancement of mucosal NO production after rectal wheat gluten challenge in patients with coeliac disease. Some of our coeliac patients displayed signs of an inflammatory reaction, as measured by NO and granulocyte markers, after rectal corn gluten challenge.

SUBMITTER: Kristjansson G

PROVIDER: S-EPMC1774524 | biostudies-literature | 2005 Jun

REPOSITORIES: biostudies-literature

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Gut mucosal granulocyte activation precedes nitric oxide production: studies in coeliac patients challenged with gluten and corn.

Kristjánsson G G Högman M M Venge P P Hällgren R R

Gut 20050601 6

<h4>Background and aims</h4>To elucidate the dynamics of nitric oxide (NO) production induced by rectal gluten challenge and the relation between NO production and mucosal granulocyte activation.<h4>Subjects and methods</h4>Release of rectal NO was measured in 13 patients with coeliac disease and in 18 controls before and after rectal wheat gluten challenge. Rectal gas was collected with a rectal balloon using a newly developed instrument/technique, the "mucosal patch technique". The instrument ...[more]

PMID: 15888782

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Project description:BackgroundThere is an unmet need for novel treatments, such as drugs or vaccines, adjunctive to or replacing a burdensome life-long gluten-free diet for coeliac disease. The gold standard for successful treatment is a healed small intestinal mucosa, and therefore, the outcome measures in proof-of-concept studies should be based on evaluation of small intestine biopsies. We here evaluated morphometric, immunohistochemical and messenger RNA (mRNA) expression changes in coeliac disease patients challenged with gluten using PAXgene fixed paraffin-embedded biopsies.MethodsFifteen coeliac disease patients were challenged with 4 g of gluten per day for 10 weeks and 24 non-coeliac patients served as disease controls. A wide array of histological and immunohistochemical staining and mRNA-based gene expression tests (RT-qPCR and RNAseq) were carried out.ResultsDigital quantitative villous height: crypt depth ratio (VH: CrD) measurements revealed significant duodenal mucosal deterioration in all coeliac disease patients on gluten challenge. In contrast, the Marsh-Oberhuber class worsened in only 80% of coeliac patients. Measuring the intraepithelial CD3+ T-lymphocyte and lamina propria CD138+ plasma cell densities simultaneously proved to be a meaningful new measure of inflammation. Stainings for γδ T cells and IgA deposits, where previously frozen samples have been needed, were successful in PAXgene fixed paraffin-embedded samples. Messenger RNA extraction from the same paraffin-embedded biopsy block was successful and allowed large-scale qRT-PCR and RNAseq analyses for gene expression. Molecular morphometry, using the mRNA expression ratio of villous epithelium-specific gene APOA4 to crypt proliferation gene Ki67, showed a similar significant distinction between paired baseline and post-gluten challenge biopsies as quantitative histomorphometry.ConclusionRigorous digitally measured histologic and molecular markers suitable for gluten challenge studies can be obtained from a single paraffin-embedded biopsy specimen. Molecular morphometry seems to be a promising new tool that can be used in situations where assessing duodenal mucosal health is of paramount importance. In addition, the diagnostically valuable IgA deposits were now stained in paraffin-embedded specimens making them more accessible in routine clinics.

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Dataset Information

Gut mucosal granulocyte activation precedes nitric oxide production: studies in coeliac patients challenged with gluten and corn.

Background and aims

Subjects and methods

Results

Conclusion

Publications

Gut mucosal granulocyte activation precedes nitric oxide production: studies in coeliac patients challenged with gluten and corn.

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