SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung
| Autor: | Anne M. Romanic, Steven Bochnowicz, Edward F. Webb, John C. Lee, Don E. Griswold, Douglas W. P. Hay, David C. Underwood, Ruth R. Osborn, David J. Rieman, Jerry L. Adams |
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| Rok vydání: | 2000 |
| Předmět: |
MAPK/ERK pathway
Lipopolysaccharides Male Physiology Neutrophils medicine.medical_treatment Pulmonary Fibrosis p38 Mitogen-Activated Protein Kinases Fibrosis Medicine Enzyme Inhibitors Lung Cells Cultured Imidazoles Cytokine Matrix Metalloproteinase 9 Cytokines medicine.symptom Mitogen-Activated Protein Kinases Pulmonary and Respiratory Medicine p38 mitogen-activated protein kinases Hypertension Pulmonary Sialoglycoproteins Guinea Pigs Inflammation Proinflammatory cytokine Bleomycin Physiology (medical) Animals Humans Lung Diseases Obstructive Protein kinase A business.industry Interleukin-6 Tumor Necrosis Factor-alpha Interleukin-8 Cell Biology medicine.disease Neutrophilia Rats Pulmonary Alveoli Disease Models Animal Interleukin 1 Receptor Antagonist Protein Pyrimidines Rats Inbred Lew Immunology Cancer research business Interleukin-1 |
| Zdroj: | American journal of physiology. Lung cellular and molecular physiology. 279(5) |
| ISSN: | 1040-0605 |
| Popis: | The effects of a second generation p38 mitogen-activated protein kinase (MAPK) inhibitor, SB 239063 [ trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxypyridimidin-4-yl)imidazole; IC50 = 44 nM vs. p38α], 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 (IC50 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. |
| Databáze: | OpenAIRE |
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