Enoxaparin Improves the Course of Dextran Sodium Sulfate-Induced Colitis in Syndecan-1-Deficient Mice
| Autor: | Andreas Luegering, Martin Götte, Ludwig Kiesel, Wolfram Domschke, Martin K. Wild, Martin Floer, Ezeddin Salem Gassar, Torsten Kucharzik, Jan Heidemann |
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| Rok vydání: | 2010 |
| Předmět: |
Lymphoid Tissue
MAP Kinase Signaling System Neutrophils Intercellular Adhesion Molecule-1 Inflammation Biology Pharmacology Pathology and Forensic Medicine Syndecan 1 Mice Cell Adhesion medicine Animals Humans Enoxaparin RNA Small Interfering Colitis Cell adhesion Cell Proliferation Wound Healing Dextran Sulfate Heparin medicine.disease Intestines Gene Expression Regulation Gene Knockdown Techniques Immunology Fibroblast Growth Factor 2 Tumor necrosis factor alpha Syndecan-1 Caco-2 Cells medicine.symptom Wound healing Regular Articles medicine.drug |
| Zdroj: | The American Journal of Pathology. 176:146-157 |
| ISSN: | 0002-9440 |
| Popis: | Syndecan-1 (Sdc1) plays a major role in wound healing and modulates inflammatory responses. Sdc1 expression is reduced in lesions of patients with ulcerative colitis. The aim of this study was to investigate the role of Sdc1 in murine dextran sodium sulfate (DSS)-induced colitis. DSS colitis was induced in Sdc1-deficient (knockout (KO)) and wild-type mice by oral administration of 3% DSS. KO mice exhibited a significantly increased lethality as compared with wild-type controls (61 versus 5%, P < 0.05). Impaired mucosal healing and prolonged recruitment of inflammatory cells in KO mice were accompanied by significant up-regulation of tumor necrosis factor-alpha, CC chemokine ligand 3/macrophage inflammatory protein-1alpha, and vascular cell adhesion molecule-1, as determined by histological correlation between 0 and 15 days after colitis induction, TaqMan low-density array analysis, and quantitative real-time PCR. Treatment from days 7 through 14 with enoxaparin, a functional analogue of the Sdc1 heparan sulfate chains, significantly reduced lethality of KO mice due to DSS-induced colitis, which was correlated with improved mucosal healing. In vitro, Sdc1-deficient polymorphonuclear cells displayed increased adhesion to endothelial cells and intercellular adhesion molecule-1, and enoxaparin reverted adhesion to wild-type levels. Small interfering RNA-mediated knockdown of Sdc1 expression resulted in reduced basic fibroblast growth factor-mediated mitogen-activated protein kinase signaling and reduced Caco-2 cell proliferation. We conclude that Sdc1 has a protective effect during experimental colitis. The modification of missing Sdc1 function by heparin analogues may emerge as a promising anti-inflammatory approach. |
| Databáze: | OpenAIRE |
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