Anti-inflammatory effects of mitogen-activated protein kinase kinase inhibitor U0126 in an asthma mouse model.
Mitogen-activated protein kinase (MAPK) signaling cascade plays a pivotal role in the activation of inflammatory cells. Recent findings revealed that the activity of p42/44 MAPK (also known as extracellular signal-regulated kinase (ERK)) in the lungs was significantly higher in asthmatic mice than in normal controls. We hypothesized that inhibition of ERK activity may have anti-inflammatory effects in allergic asthma. BALB/c mice were sensitized with OVA and, upon OVA aerosol challenge, developed airway eosinophilia, mucus hypersecretion, elevation in cytokine and chemokine levels, up-regulation of VCAM-1 expression, and airway hyperresponsiveness. Intraperitoneal administration of U0126, a specific MAPK/ERK kinase inhibitor, significantly (p < 0.05) inhibited OVA-induced increases in total cell counts, eosinophil counts, and IL-4, IL-5, IL-13, and eotaxin levels recovered in bronchoalveolar lavage fluid in a dose-dependent manner. U0126 also substantially (p < 0.05) reduced the serum levels of total IgE and OVA-specific IgE and IgG1. Histological studies show that U0126 dramatically inhibited OVA-induced lung tissue eosinophilia, airway mucus production, and expression of VCAM-1 in lung tissues. In addition, U0126 significantly (p < 0.05) suppressed OVA-induced airway hyperresponsiveness to inhaled methacholine in a dose-dependent manner. Western blot analysis of whole lung lysates shows that U0126 markedly attenuated OVA-induced tyrosine phosphorylation of ERK1/2. Taken together, our findings implicate that inhibition of ERK signaling pathway may have therapeutic potential for the treatment of allergic airway inflammation.
Duan
Wei
W
Department of Pharmacology, National University of Singapore, Singapore.
Chan
Jasmine H P
JH
Wong
Chui Hong
CH
Leung
Bernard P
BP
Wong
W S Fred
WS
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy*; D016535:Bronchial Hyperreactivity / Q000209:etiology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002070:Butadienes / Q000494:pharmacology*; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D009093:Mucus / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology*; D010047:Ovalbumin / Q000276:immunology; D010766:Phosphorylation; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
D000893:Anti-Inflammatory Agents; D002070:Butadienes; D016207:Cytokines; D004791:Enzyme Inhibitors; D007074:Immunoglobulin G; D009570:Nitriles; C113580:U 0126; D019010:Vascular Cell Adhesion Molecule-1; D010047:Ovalbumin; D020928:Mitogen-Activated Protein Kinases