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A novel topical PPARγ agonist induces PPARγ-activity in ulcerative colitis mucosa and prevents and reverses inflammation in induced-colitis models
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.ORCID iD: 0000-0001-8817-6403
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.ORCID iD: 0000-0002-6820-0215
Translational Cancer Research, Cancer Center at Medicon Village, Lund University, Lund, Sweden.
Translational Cancer Research, Cancer Center at Medicon Village, Lund University, Lund, Sweden.
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2018 (English)In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 24, no 4, p. 792-805Article in journal (Refereed) Published
Abstract [en]

Background: Peroxisome proliferator-activated receptor-gamma (PPARγ) exerts anti-inflammatory effects and is therefore a potential target in ulcerative colitis (UC). A novel PPARγ agonist (AS002) developed for local action was evaluated ex vivo in biopsies from UC patients and in vivo in mice with low-grade dextran sodium sulfate (DSS)- and trinitrobenzene sulfonic acid (TNBS)-induced colitis.Methods: Colonic biopsies from UC patients (n = 18) and healthy controls (n = 6) were incubated with AS002 or rosiglitazone (positive control) to measure mRNA expression of the PPARγ-responsive gene ADIPOPHILIN and protein levels of UC-related cytokines (enzyme-linked immunosorbent assay). AS002 absorption was determined in the colonic mucosa of UC patients. DSS-colitis mice received PPARγ agonists or vehicle daily by intrarectal administration starting 2 days before induction of colitis (preventive) or from days 3 to 8 (curative). Myeloperoxidase (MPO) and cytokine levels in colonic mucosa were determined. In addition, AS002 effects were studied in TNBS colitis.Results: AS002 displayed an absorption pattern of a lipophilic drug totally metabolized in the mucosa. AS002 and rosiglitazone increased ADIPOPHILIN mRNA expression (3-fold) and decreased TNF-α, IL-1β, and IL-13 levels in human UC biopsies. In DSS, in both preventive and curative treatment and in TNBS colitis, AS002 protected against macroscopic and histological damage and lowered MPO and TNF-α, IL-1β, and IL-13 levels.Conclusions: AS002 triggers anti-inflammatory PPARγ activity in the human colonic mucosa of UC patients and prevents and reverses colitis in mice. Our data suggest that AS002 has potential for topical maintenance treatment of UC, which warrants further studies in vivo in patients.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2018. Vol. 24, no 4, p. 792-805
Keywords [en]
IBD, ulcerative colitis, animal model, PPAR gamma, intestine
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:liu:diva-145641DOI: 10.1093/ibd/izx079ISI: 000428546400013OAI: oai:DiVA.org:liu-145641DiVA, id: diva2:1189461
Available from: 2018-03-10 Created: 2018-03-10 Last updated: 2018-05-17

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Keita, Åsa V.Söderholm, Johan D.

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Da Silva, StéphanieKeita, Åsa V.Söderholm, Johan D.
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Division of Surgery, Orthopedics and OncologyFaculty of Medicine and Health SciencesDepartment of Surgery in Linköping
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Inflammatory Bowel Diseases
Gastroenterology and Hepatology

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