Dehydroxymethylepoxyquinomicin (DHMEQ), a novel NF-kappaB inhibitor, inhibits allergic inflammation and airway remodelling in murine models of asthma

• Published in: Clinical and experimental allergy 2012-08, Vol.42 (8), p.1273-1281
• Main Authors: Shimizu, K., Konno, S., Ozaki, M., Umezawa, K., Yamashita, K., Todo, S., Nishimura, M.
• Format: Article
• Language: English
• Subjects: Airway Remodeling - drug effects; Animals; Asthma; Asthma - drug therapy; Asthma - metabolism; Asthma - pathology; Benzamides - administration & dosage; Benzamides - pharmacology; Biological and medical sciences; Bronchoalveolar Lavage Fluid - immunology; Cells, Cultured; Chronic obstructive pulmonary disease, asthma; Cyclohexanones - administration & dosage; Cyclohexanones - pharmacology; Cytokines; Cytokines - immunology; Cytokines - metabolism; DHMEQ; Disease Models, Animal; Eosinophils - immunology; Eosinophils - pathology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; inflammation; Inflammation - drug therapy; Inflammation - metabolism; Inflammation - pathology; Inflammation Mediators - metabolism; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Medical research; Medical sciences; Mice; Mice, Inbred BALB C; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-κB; Pneumology; remodelling; Respiratory Hypersensitivity - drug therapy; Respiratory Hypersensitivity - metabolism; Rodents
• ISSN: 0954-7894; 1365-2222
• DOI: 10.1111/j.1365-2222.2012.04007.x

Summary Background Dehydroxymethylepoxyquinomicin (DHMEQ) is a newly developed compound that inhibits nuclear factor κB activation and is reported to ameliorate animal models of various inflammatory diseases without significant adverse effects. Because nuclear factor κB is a transcription factor that plays a critical role in the pathophysiology of asthma, DHMEQ may be of therapeutic benefit in asthma. Objective The purpose of this study was to evaluate the effects of DHMEQ on airway inflammation and remodelling in murine models of asthma. Methods The BALB/c mice were sensitized and then challenged acutely or chronically with ovalbumin and administered DHMEQ intraperitoneally before each challenge. Inflammation of airways, lung histopathology and airway hyper responsiveness to methacholine challenge were evaluated. In addition, the effect of DHMEQ on production of cytokines and eotaxin‐1 by murine splenocytes, human peripheral blood mononuclear cells and bronchial epithelial cells was investigated. Results Airway hyper responsiveness was ameliorated in both acutely and chronically challenged models by treatment with DHMEQ. DHMEQ significantly reduced eosinophilic airway inflammation and levels of Th2 cytokines in bronchoalveolar lavage fluid in the acute model. It also inhibited parameters of airway remodelling including mucus production, peribronchial fibrosis and the expression of α‐smooth muscle actin. Moreover, the production of Th2 cytokines from murine splenocytes and human peripheral blood mononuclear cells and the production of eotaxin‐1 by bronchial epithelial cells were inhibited by DHMEQ. Conclusions and Clinical Relevance These results indicate that DHMEQ inhibits allergic airway inflammation and airway remodelling in murine models of asthma. DHMEQ may have therapeutic potential in the treatment of asthma.