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

Abstract

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.

• Authors: D C Underwood, R R Osborn, S Bochnowicz, E F Webb, D J Rieman, J C Lee, A M Romanic, J L Adams, D W Hay, D E Griswold
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 279 Issue 5 Pg. L895-902 (Nov 2000) ISSN: 1040-0605 [Print] United States
• PMID: 11053025 (Publication Type: Journal Article)

Chemical References

• Cytokines
• Enzyme Inhibitors
• IL1RN protein, human
• Imidazoles
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-1
• Interleukin-6
• Interleukin-8
• Lipopolysaccharides
• Pyrimidines
• Sialoglycoproteins
• Tumor Necrosis Factor-alpha
• Bleomycin
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Matrix Metalloproteinase 9
• SB 239063

Topics

• Animals
• Bleomycin (toxicity)
• Cells, Cultured
• Cytokines (biosynthesis, blood)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Guinea Pigs
• Humans
• Hypertension, Pulmonary (chemically induced, prevention & control)
• Imidazoles (pharmacology)
• Inflammation (physiopathology, prevention & control)
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-1 (blood)
• Interleukin-6 (blood)
• Interleukin-8 (blood)
• Lipopolysaccharides (toxicity)
• Lung (drug effects, physiopathology)
• Lung Diseases, Obstructive (physiopathology)
• Male
• Matrix Metalloproteinase 9 (metabolism)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Neutrophils (drug effects, physiology)
• Pulmonary Alveoli (drug effects, immunology)
• Pulmonary Fibrosis (chemically induced, prevention & control)
• Pyrimidines (pharmacology)
• Rats
• Rats, Inbred Lew
• Sialoglycoproteins (blood)
• Tumor Necrosis Factor-alpha (metabolism)
• p38 Mitogen-Activated Protein Kinases