Effects of ciclamilast, a new PDE 4 PDE4 inhibitor, on airway hyperresponsiveness, PDE4D expression and airway inflammation in a murine model of asthma.
PDE4 (phosphodiesterase-4) plays a critical role in pathogenesis of allergic asthma and chronic obstructive pulmonary disease (COPD). PDE4 inhibitors are presently under clinical development for the treatment of asthma and/or COPD. Ciclamilast, a new PDE4 inhibitor, is a piclamilast (RP 73401) structural analogue, but has a more potent inhibitory effect on PDE4 and inflammation in the airway tissues and less side effects than that of piclamilast. In this study, we elucidate primarily on the roles of compound on PDE4 enzyme in physiological and pathological processes in a mouse model of asthma. The sensitized/challenged mice were reexposed to ovalbumin and airway response to inhaled methacholine was monitored. Orally administration of ciclamilast, in a dose-dependent manner, significantly inhibited changes in lung resistance and lung dynamic compliance, as well as upregulation of cAMP-PDE activity, increase of PDE4D mRNA expression, but not PDE4B from lung tissue in the murine model. In addition, the compound dose-dependently reduced mRNA expression of eotaxin, tumor necrosis factor (TNF)-alpha and interleukin (IL)-4, but slightly increased mRNA expression of interferon (IFN)-gamma from lung tissue. Further, levels of eotaxin, TNF-alpha and IL-4, and eosinophil and neutrophil accumulation in bronchoalveolar lavage fluid were also significantly reduced. Pathological examination, goblet cell hyperplasia and inflammatory cells infiltration in lung tissue were suppressed by treatment with ciclamilast. A significant correlation was observed between the increases in PDE4D mRNA expression and airway hyperresponsiveness. These studies confirm that inhibitory effect of ciclamilast on airway hyperresponsiveness includes its inhibiting PDE4D mRNA expression, down-modulating PDE4 activity, anti-inflammation and anti-mucus hypersecretion, and ciclamilast may have therapeutic potential for the treatment of asthma.
Deng
Yang-mei
YM
Zhejiang Respiratory Drugs Research Laboratory Of State Food And Drug Administration, Medical Science College Of Zhejiang University, Hangzhou, PR China.
Xie
Qiang-min
QM
Tang
Hui-fang
HF
Sun
Jian-gang
JG
Deng
Jun-fang
JF
Chen
Ji-qiang
JQ
Yang
Shui-you
SY
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D001549:Benzamides / Q000494:pharmacology*; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D001991:Bronchitis / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004802:Eosinophilia / Q000473:pathology / Q000517:prevention & control; D005260:Female; D015870:Gene Expression / Q000235:genetics; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016210:Methacholine Chloride / Q000008:administration & dosage / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D000485:Allergens; D000893:Anti-Inflammatory Agents; D001549:Benzamides; D018925:Chemokines; D016207:Cytokines; D007527:Isoenzymes; C515489:N-(3,5-dichloro-4-pyrid-4-yl)-3-cyclopentyl-oxy-4-methylbenzamide; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D016210:Methacholine Chloride; D003907:Dexamethasone; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4