SB 239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatory cytokines, MMP-9, and fibrosis in lung

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 279; no. 5; pp. 895 - L902
• Main Authors: Underwood, David C, Osborn, Ruth R, Bochnowicz, Steven, Webb, Edward F, Rieman, David J, Lee, John C, Romanic, Anne M, Adams, Jerry L, Hay, Douglas W. P, Griswold, Don E
• Format: Journal Article
• Language: English
• Published: United States 01.11.2000
• Subjects: Animals; Bleomycin - toxicity; Cells, Cultured; Cytokines - biosynthesis; Cytokines - blood; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Guinea Pigs; Humans; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - prevention & control; Imidazoles - pharmacology; Inflammation - physiopathology; Inflammation - prevention & control; Interleukin 1 Receptor Antagonist Protein; Interleukin-1 - blood; Interleukin-6 - blood; Interleukin-8 - blood; Lipopolysaccharides - toxicity; Lung - drug effects; Lung - physiopathology; Lung Diseases, Obstructive - physiopathology; Male; Matrix Metalloproteinase 9 - metabolism; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Neutrophils - drug effects; Neutrophils - physiology; p38 Mitogen-Activated Protein Kinases; Pulmonary Alveoli - drug effects; Pulmonary Alveoli - immunology; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - prevention & control; Pyrimidines - pharmacology; Rats; Rats, Inbred Lew; Sialoglycoproteins - blood; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.2000.279.5.l895

Departments of 1  Pulmonary Pharmacology, 2  Bone and Cartilage Biology, 3  Cardiovascular Pharmacology, and 4  Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406 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; IC 50  = 44 nM vs. p38 ], 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. chronic obstructive pulmonary disease; interleukin-6; bleomycin; alveolar macrophage; mitogen-activated protein kinase; matrix metalloproteinase-9