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SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung.
Underwood, D C; Osborn, R R; Bochnowicz, S; Webb, E F; Rieman, D J; Lee, J C; Romanic, A M; Adams, J L; Hay, D W; Griswold, D E.
Afiliación
  • Underwood DC; Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Am J Physiol Lung Cell Mol Physiol ; 279(5): L895-902, 2000 Nov.
Article en En | MEDLINE | ID: mdl-11053025
The effects of a second generation p38 mitogen-activated protein kinase (MAPK) inhibitor, SB 239063 [trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxypyridim idi n-4-yl)imidazole; IC(50) = 44 nM vs. p38 alpha], were assessed in models that represent different pathological aspects of chronic obstructive pulmonary disease (COPD) [airway neutrophilia, enhanced cytokine formation and increased matrix metalloproteinase (MMP)-9 activity] and in a model of lung fibrosis. Airway neutrophil infiltration and interleukin (IL)-6 levels, assessed by bronchoalveolar lavage 48 h after lipopolysaccharide (LPS) inhalation, were inhibited dose dependently by 3-30 mg/kg of SB 239063 given orally twice a day. In addition, SB 239063 (30 mg/kg orally) attenuated IL-6 bronchoalveolar lavage fluid concentrations (>90% inhibition) and MMP-9 activity (64% inhibition) assessed 6 h after LPS exposure. In guinea pig cultured alveolar macrophages, SB 239063 inhibited LPS-induced IL-6 production (IC(50) of 362 nM). In a bleomycin-induced pulmonary fibrosis model in rats, treatment with SB 239063 (2.4 or 4.8 mg/day via osmotic pump) significantly inhibited bleomycin-induced right ventricular hypertrophy (indicative of secondary pulmonary hypertension) and increases in lung hydroxyproline synthesis (indicative of collagen synthesis and fibrosis). Therefore, SB 239063 demonstrates activity against a range of sequelae commonly associated with COPD and fibrosis, supporting the therapeutic potential of p38 MAPK inhibitors such as SB 239063 in chronic airway disease.
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fibrosis Pulmonar / Pirimidinas / Lipopolisacáridos / Citocinas / Metaloproteinasa 9 de la Matriz / Proteínas Quinasas Activadas por Mitógenos / Inhibidores Enzimáticos / Imidazoles / Enfermedades Pulmonares Obstructivas / Neutrófilos Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Am J Physiol Lung Cell Mol Physiol Asunto de la revista: BIOLOGIA MOLECULAR / FISIOLOGIA Año: 2000 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Buscar en Google
Añadir a Mi BVS
Imprimir
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fibrosis Pulmonar / Pirimidinas / Lipopolisacáridos / Citocinas / Metaloproteinasa 9 de la Matriz / Proteínas Quinasas Activadas por Mitógenos / Inhibidores Enzimáticos / Imidazoles / Enfermedades Pulmonares Obstructivas / Neutrófilos Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Am J Physiol Lung Cell Mol Physiol Asunto de la revista: BIOLOGIA MOLECULAR / FISIOLOGIA Año: 2000 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos