Involvement of endogenous endothelins on experimental arthritis in mice.
Endothelins (ETs) are peptides produced by a wide variety of cells that exert their functions through ETA and ETB receptors. Increased ET-1 levels were found in plasma andsynovial fluids of patients with rheumatoid arthritis, an autoimmune disease characterized by cell influx, edema formation and joint destruction. The aim of this study was to evaluate the role of ETs in knee joint inflammation induced by zymosan. We evaluated in C57BL/6 mice the effect of intra-articular (i.a.) injection of ET-1 (10 pmol/cav) in C57BL/6 mice induced at 6 h an increase on cellular migration, mainly due to neutrophil accumulation (sal 0.25±0.005 x ET-1 0.93±0.007 x 105 cells/knee) and on edema formation (sal 0.12±0.04 x ET-1 0.47±0.09 ? mm/knee), that peaked within 6 h and returned to basal levels at 24 h. A selective ETB receptor agonist, sarafotoxin S6c (S6c; 30 pmol/cav; i.a.), induced at 6 h a significant increase on cellular recruitment, mainly by neutrophil accumulation (sal 0.13±0.018 x S6c 0.661±0.134 x 105 cells/knee) and on edema formation (sal 0.14±0.04 x S6c 0.37±0.05 ? mm/knee). Next, we evaluated the effect of i.a. injection of ETA and ETB receptor antagonists (BQ-123 and BQ-788, 0,15-150 pmol/cav, respectively) on zymosan- induced arthritis in C57BL/6 mice. Pre-treatment with BQ-123 and BQ-788 (15 pmol/cav) reduced 6 h zymosaninducedaccumulation of neutrophil (64 and 73 % respectively) edema formation (40 and 61 % respectively) and TNF-a levels (39 and 51 % respectively); as well as 24 h zymosaninduced neutrophil influx (65 and 61 % respectively), edema formation (43 and 52 % respectively) and CXCL1 levels (12 and 11 % respectively). Moreover, 6 and 24 h afterzymosan stimulation we observed a significant decrease on ETB receptor expression when compared to control group, whereas ETA receptor expression was reduced only within 24 hafter stimulation. Taken together, this results point to a participation of ETs on knee joint inflammation.
Advisor:Carmen Penido Monteiro; Maria das Graças Muller de Oliveira Henriques
School:Faculdades Oswaldo Cruz
Source Type:Master's Thesis
Date of Publication:08/01/2007