title: Bilirubin prevents acute DSS-induced colitis by inhibiting leukocyte infiltration and suppressing upregulation of inducible nitric oxide synthase.
abstract: Bilirubin is thought to exert anti-inflammatory effects by inhibiting vascular cell adhesion molecule-1 (VCAM-1)-dependent leukocyte migration and by suppressing the expression of inducible nitric oxide synthase (iNOS). As VCAM-1 and iNOS are important mediators of tissue injury in the dextran sodium sulfate (DSS) murine model of inflammatory colitis, we examined whether bilirubin prevents colonic injury in DSS-treated mice. Male C57BL/6 mice were administered 2.5% DSS in the drinking water for 7 days, while simultaneously receiving intraperitoneal injections of bilirubin (30 mg/kg) or potassium phosphate vehicle. Disease activity was monitored, peripheral blood counts and serum nitrate levels were determined, and intestinal specimens were analyzed for histological injury, leukocyte infiltration, and iNOS expression. The effect of bilirubin on IL-5 production by HSB-2 cells and on Jurkat cell transendothelial migration also was determined. DSS-treated mice that simultaneously received bilirubin lost less body weight, had lower serum nitrate levels, and exhibited reduced disease severity than vehicle-treated animals. Concordantly, histopathological analyses revealed that bilirubin-treated mice manifested significantly less colonic injury, including reduced infiltration of eosinophils, lymphocytes, and monocytes, and diminished iNOS expression. Bilirubin administration also was associated with decreased eosinophil and monocyte infiltration into the small intestine, with a corresponding increase in peripheral blood eosinophilia. Bilirubin prevented Jurkat migration but did not alter IL-5 production. In conclusion, bilirubin prevents DSS-induced colitis by inhibiting the migration of leukocytes across the vascular endothelium and by suppressing iNOS expression.
authors.affiliation: Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio zuckersd@ucmail.uc.edu.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Zucker
authors.affiliation: Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Vogel
authors.affiliation: Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Kindel
authors.affiliation: Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Darcey L H
authors.initials: DL
authors.lastname: Smith
authors.affiliation: Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Gila
authors.initials: G
authors.lastname: Idelman
authors.affiliation: Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Uri
authors.initials: U
authors.lastname: Avissar
authors.affiliation: Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Kakarlapudi
authors.affiliation: Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Masnovi
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000008:administration & dosage / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D003092:Colitis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003603:Cytotoxins / Q000494:pharmacology; D016264:Dextran Sulfate / Q000494:pharmacology; D015848:Interleukin-5 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D020011:Protective Agents / Q000008:administration & dosage / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
chemical_list: D003603:Cytotoxins; D015848:Interleukin-5; D020011:Protective Agents; D019010:Vascular Cell Adhesion Molecule-1; D016264:Dextran Sulfate; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001663:Bilirubin
keywords: DSS colitis; VCAM-1; bilirubin; eosinophil; iNOS