OP0228 Protective Effect of LPA1 and 3 Receptor Antagonism in Experimental Skin Fibrosis is Linked to LPA Activity in Dermal Fibroblasts of SSC Patients
| Autor: | H. Ruetten, J. H. W. Distler, S. Illiano, M. Schaefer, Christian Beyer, J.-P. Bidouard, Oliver Distler, L. Ledein, Clara Dees, P. Janiak, Alfiya Distler |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
integumentary system
business.industry Immunology Pharmacology medicine.disease Bleomycin Pertussis toxin General Biochemistry Genetics and Molecular Biology chemistry.chemical_compound Rheumatology chemistry In vivo Fibrosis Lysophosphatidic acid Immunology and Allergy Medicine Platelet activation business Receptor Myofibroblast |
| Zdroj: | Annals of the Rheumatic Diseases. 72:A129.2-A129 |
| ISSN: | 1468-2060 0003-4967 |
| DOI: | 10.1136/annrheumdis-2013-eular.433 |
| Popis: | Background Lysophosphatidic acid (LPA) is a phospholipid generated by phospholipase D-mediated cleavage of phosphatidylcholine, mainly in adipocytes, fibroblasts or activated platelets. Knock down studies of the LPA1 receptor in lung and kidney fibrosis suggest a role of LPA in fibrosis. Objectives To investigate the potential of LPA1/3 receptor antagonism in Systemic Sclerosis (SSc) using both in vitro and in vivo approaches. Methods Primary cultures of dermal fibroblasts from patients with SSc and healthy controls were used for expression analysis and functional (Ca2+ + cytokines measurement) in vitro studies (n=5 each). In some experiments, cells were pre-treated overnight with Pertussis Toxin (50 ng/ml) to evaluate Gi protein involvement in LPA-induced Ca2+ response. The bleomycin skin model and the tight skin mouse model (Tsk-1) were used to assess the effects of the LPA1/3 antagonist SAR100842 (30 mg/kg BID) in vivo (n= 7 for each group) using established endpoints. Results SSc skin fibroblasts expressed mainly LPA1 receptors and LPA4 receptors to a lower extent. The SSc fibroblasts demonstrated a greater sensitivity to LPA-induced increase in cytosolic Ca2+ than normal dermal fibroblasts. The LPA-induced increase in cytosolic Ca2+ was inhibited by Pertussis Toxin (supporting the evidence of a Gi coupling) and was also fully antagonized with SAR100842 (confirming the role of LPA1 receptors). LPA also induced expression of aSMA in SSc as well as markers of fibrosis like PAI-1, cytokines (IL-6, IL-8, CXCL-1, CCL-2) and markers of the Wnt pathway (SFRP4 and WNT2). In the mouse model of bleomycin-induced skin fibrosis, using a therapeutic protocol, LPA1/3 antagonism by SAR100842 reversed significantly (p |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|