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Role of alkaline phosphatase in colitis in man and rats
  1. Annemarie Tuin (a.tuin{at}rug.nl)
  1. Dept. of Pharmacokinetics & Drug Delivery, University of Groningen, Netherlands
    1. Klaas Poelstra (k.poelstra{at}rug.nl)
    1. Dept. of Pharmacokinetics & Drug Delivery, University of Groningen, Netherlands
      1. Alie de Jager-Krikken
      1. Dept. of Pharmacokinetics & Drug Delivery, University of Groningen, Netherlands
        1. Lisette Bok
        1. Dept. of Gastroenterology & Hepatology, University Medical Centre Groningen, Netherlands
          1. Willem Raaben
          1. AM-Pharma, Netherlands
            1. Markwin P. Velders
            1. AM-Pharma, Netherlands
              1. Gerard Dijkstra (g.dijkstra{at}int.umcg.nl)
              1. Dept. of Gastroenterology & Hepatology, University Medical Centre Groningen, Netherlands

                Abstract

                Background & Aims: Crohn's disease (CD) and ulcerative colitis (UC) are chronic multifactorial inflammatory bowel diseases with unknown etiology, but a deregulated mucosal immune response to gut-derived bacterial antigens is thought to be involved. Toll-like receptor ligands, especially lipopolysaccharide (LPS), contribute to the maintenance of the disease. We have previously shown that the enzyme alkaline phosphatase (AP) is able to detoxify LPS and the aim of this study was to examine a possible role in inflammatory bowel diseases.

                Methods: Intestinal AP (iAP) mRNA expression and LPS-dephosphorylation in intestinal biopsies of control persons and IBD patients were examined, and we subsequently studied the effect of orally administered iAP-tablets on the progression of dextran sodium sulphate-induced colitis in rats.

                Results: In healthy persons, iAP mRNA and enzyme activity was high in the ileum relative to the colon. In UC and Crohn's patients iAP mRNA expression was found markedly reduced when inflamed tissue was compared to non-inflamed tissue. Oral administration of iAP-tablets to colitic rats resulted in a significant attenuation of colonic inflammation as reflected by reduced mRNA levels for TNFα, IL-1β, IL-6 and iNOS, a reduced iNOS-staining and inflammatory cell influx, and a significantly improved morphology of the intestinal wall.

                Conclusions: The present study shows that epithelial iAP mRNA expression is reduced in both UC and Crohn's patients. The rat model demonstrates that oral administration of active iAP-enzymes in the intestinal tract, results in a significant reduction of inflammation. This provides new insight on IBD pathology and a novel treatment approach to this severe inflammatory disease.

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