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2.
J Med Chem ; 47(6): 1319-21, 2004 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-14998320
3.
J Immunol ; 169(11): 6435-44, 2002 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-12444152

RESUMO

Much evidence implicates IL-8 as a major mediator of inflammation and joint destruction in rheumatoid arthritis. The effects of IL-8 and its related ligands are mediated via two receptors, CXCR1 and CXCR2. In the present study, we demonstrate that a potent and selective nonpeptide antagonist of human CXCR2 potently inhibits (125)I-labeled human IL-8 binding to, and human IL-8-induced calcium mobilization mediated by, rabbit CXCR2 (IC(50) = 40.5 and 7.7 nM, respectively), but not rabbit CXCR1 (IC(50) = >1000 and 2200 nM, respectively). These data suggest that the rabbit is an appropriate species in which to examine the anti-inflammatory effects of a human CXCR2-selective antagonist. In two acute models of arthritis in the rabbit induced by knee joint injection of human IL-8 or LPS, and a chronic Ag (OVA)-induced arthritis model, administration of the antagonist at 25 mg/kg by mouth twice a day significantly reduced synovial fluid neutrophils, monocytes, and lymphocytes. In addition, in the more robust LPS- and OVA-induced arthritis models, which were characterized by increased levels of proinflammatory mediators in the synovial fluid, TNF-alpha, IL-8, PGE(2), leukotriene B(4), and leukotriene C(4) levels were significantly reduced, as was erythrocyte sedimentation rate, possibly as a result of the observed decreases in serum TNF-alpha and IL-8 levels. In vitro, the antagonist potently inhibited human IL-8-induced chemotaxis of rabbit neutrophils (IC(50) = 0.75 nM), suggesting that inhibition of leukocyte migration into the knee joint is a likely mechanism by which the CXCR2 antagonist modulates disease.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/imunologia , Artrite Experimental/prevenção & controle , Receptores de Interleucina-8B/antagonistas & inibidores , Ureia/farmacologia , Doença Aguda , Animais , Artrite Experimental/etiologia , Artrite Reumatoide/etiologia , Artrite Reumatoide/imunologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Doença Crônica , Feminino , Humanos , Técnicas In Vitro , Interleucina-8/administração & dosagem , Interleucina-8/imunologia , Interleucina-8/metabolismo , Lipopolissacarídeos/toxicidade , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Coelhos , Receptores de Interleucina-8B/genética , Receptores de Interleucina-8B/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Ureia/análogos & derivados
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