Dehydroxymethylepoxyquinomicin (DHMEQ), a novel NF-kappaB inhibitor, inhibits allergic inflammation and airway remodelling in murine models of asthma.
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
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.
First Department of Medicine, Hokkaido University School of Medicine, Kita-ku, Sapporo, Japan.
K
K
Shimizu
S
S
Konno
M
M
Ozaki
K
K
Umezawa
K
K
Yamashita
S
S
Todo
M
M
Nishimura
D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002478:Cells, Cultured; D003512:Cyclohexanones / Q000008:administration & dosage / Q000494:pharmacology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000378:metabolism
D001549:Benzamides; D003512:Cyclohexanones; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; C464444:dehydroxymethylepoxyquinomicin