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

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 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.

Bosentan, an endothelin receptor antagonist, ameliorates collagen-induced arthritis: the role of TNF-α in the induction of endothelin system genes

“…Bosentan-treated mice presented a reduction in the following inflammatory parameters: edema, pain, joint movement, granulocyte and mononuclear cell infiltration into the joint tissue, bone and cartilage destruction, the production of pro-inflammatory cytokines and neutrophil migration. These results are in accordance with previous results that demonstrated that ET-1 mediates inflammatory events of zymosan-induced articular inflammation, including edema and neutrophil infiltration [35]. Moreover, ETs seem to be involved in pain in antigen-induced arthritis in mice [22,36].…”

“…Indeed, as mentioned above, the levels of ET-1 were higher in RA patients than in osteoarthritic patients [15,16]. Furthermore, an increased expression of preproET in zymosan-and antigen-induced articular inflammation was found in mice [22,35]. Additionally, ETA and ETB receptors are functionally expressed in synovial tissue [23,34].…”

Central mediators of the zymosan-induced febrile response

“…The ET A and ET B receptor antagonist administration reduced edema formation, neutrophil influx, and TNF-α production in rat knee joints [45]. These results suggest that zymosan can induce the production of ET-1, at least locally.…”

Bosentan, a mixed endothelin receptor antagonist, inhibits superoxide anion-induced pain and inflammation in mice

“…Focusing on inflammation and pain, ET-1 upregulates the expression of adhesion molecules on endothelial cells and fibroblasts, increases neutrophil adhesion and migration, stimulates cytokine production through activation of NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells), increases microvascular permeability, and enhances pain sensitivity (Conte Fde et al 2008;Verri et al 2008;Ohanian et al 2012;Zarpelon et al 2012). The sources of ET-1 include vascular endothelial cells, macrophages, neutrophils, fibroblasts, and neurons (Barton and Yanagisawa 2008), and these cells also present endothelin receptors that are upregulated during inflammation, emphasizing the role of the endothelin system on maladaptive inflammatory responses and diseases (Pomonis et al 2001;Motte et al 2006;Lau et al 2014).…”