Endothelins modulate inflammatory reaction in zymosan-induced arthritis: participation of LTB4, TNF-alpha, and CXCL-1.
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 microg/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-alpha production within 6 h, keratinocyte-derived chemokine/CXCL1 production within 24 h, and leukotriene B(4) 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.
Departamento de Farmacologia Aplicada, Farmanguinhos, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
Fernando de Paiva
Fde P
Conte
Christina
C
Barja-Fidalgo
Waldiceu A
WA
Verri
Fernando Queiroz
FQ
Cunha
Giles A
GA
Rae
Carmen
C
Penido
Maria das Graças M O
Md
Henriques
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001168:Arthritis / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D000077300:Bosentan; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D054360:Chemokine CXCL1 / Q000378:metabolism*; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D015151:Immunoblotting; D007155:Immunologic Factors / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007719:Knee Joint / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects; D007975:Leukotriene B4 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology; D015054:Zymosan
D000959:Antihypertensive Agents; D054360:Chemokine CXCL1; D018925:Chemokines; C475895:Cxcl1 protein, mouse; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007155:Immunologic Factors; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D017466:Receptors, Endothelin; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C074302:keratinocyte-derived chemokines; D007975:Leukotriene B4; C086539:BQ 788; D015054:Zymosan; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)