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Published online before print May 30, 2008

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(Journal of Leukocyte Biology. 2008;84:652-660.)
© 2008 by Society for Leukocyte Biology

Endothelins modulate inflammatory reaction in zymosan-induced arthritis: participation of LTB₄, TNF-, and CXCL-1

Fernando de Paiva Conte^*, Christina Barja-Fidalgo, Waldiceu A. Verri, Jr., Fernando Queiroz Cunha, Giles A. Rae, Carmen Penido^*,1 and Maria das Graças M. O. Henriques^*,1,2

^* Departamento de Farmacologia Aplicada, Farmanguinhos, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil;
Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Brazil;
Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil; and
Departamento de Farmacologia, Instituto de Biologia, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil

² Correspondence: Farmacologia Aplicada, Farmanguinhos–Fiocruz, Rua Sizenando Nabuco, 100, Manguinhos, Rio de Janeiro, RJ, Brazil. CEP: 21041-250. E-mail: gracahenriques{at}fiocruz.br

ABSTRACT

Endothelins (ETs) are involved in inflammatory events, including pain, fever, edema, and cell migration. ET-1 levels are increased in plasma and synovial membrane of rheumatoid arthritis (RA) patients, but the evidence that ETs participate in RA physiopathology is limited. The present study investigated the involvement of ETs in neutrophil accumulation and edema formation in the murine model of zymosan-induced arthritis. Intra-articular (i.a.) administration of selective ET_A or ET_B receptor antagonists (BQ-123 and BQ-788, respectively; 15 pmol/cavity) prior to i.a. zymosan injection (500 µg/cavity) markedly reduced knee-joint edema formation and neutrophil influx to the synovial cavity 6 h and 24 h after stimulation. Histological analysis showed that ET_A or ET_B receptor blockade suppressed zymosan-induced neutrophil accumulation in articular tissue at 6 h. Likewise, dual blockade of ET_A/ET_B with bosentan (10 mg/kg, i.v.) also reduced edema formation and neutrophil counts 6 h after zymosan stimulation. Pretreatment with BQ-123 or BQ-788 (i.a.; 15 pmol/cavity) also decreased zymosan-induced TNF- production within 6 h, keratinocyte-derived chemokine/CXCL1 production within 24 h, and leukotriene B₄ at both time-points. Consistent with the demonstration that ET receptor antagonists inhibit zymosan-induced inflammation, i.a. injection of ET-1 (1–30 pmol/cavity) or sarafotoxin S6c (0.1–30 pmol/cavity) also triggered edema formation and neutrophil accumulation within 6 h. Moreover, knee-joint synovial tissue expressed ET_A and ET_B receptors. These findings suggest that endogenous ETs contribute to knee-joint inflammation, acting through ET_A and ET_B receptors and modulating edema formation, neutrophil recruitment, and production of inflammatory mediators.

Key Words: neutrophil • cytokine • chemokine • lipid mediator • bosentan • sarafotoxin s6c