ASP3258 is a novel, orally active, selective
phosphodiesterase (
PDE) 4 inhibitor which has an improved therapeutic window over second generation compounds such as
roflumilast and
cilomilast. Here, we investigated the effect of
ASP3258 on cigarette
smoke exposure-induced
lung injury in guinea pigs, a well-defined model for
chronic obstructive pulmonary disease (
COPD).
COPD-like
lung injury was induced by repeated cigarette
smoke exposure (10 cigarettes/day, 5 days/week, for 4 weeks). Orally administered
ASP3258 (0.3, 1, and 3mg/kg) dose-dependently suppressed pulmonary accumulation of mononuclear cells and neutrophils, and the inhibitory effect of
ASP3258 (1mg/kg) was almost the same as that of
roflumilast (1mg/kg). In contrast, a
glucocorticoid prednisolone (10mg/kg, p.o.) did not show any effect. Histological examination revealed that
ASP3258 treatment significantly inhibited infiltration of neutrophils and macrophages into either or both alveolar or peribronchiolar areas, as well as hyperplastic and squamous metaplastic changes of epithelium in the bronchi. Decreasing trends in histological scores for accumulation of lymphocytes in the alveoli and alveolar wall thickening were also observed in ASP3258-treated animals. Further,
ASP3258 attenuated augmentation of
matrix metalloproteinase-9 activity in the bronchoalveolar lavage fluid. These findings suggest that
ASP3258 has therapeutic potential for treating
COPD not only through inhibition of pulmonary cellular accumulation but also by preventing lung structural alterations initiated by repeated cigarette
smoke exposure. To our knowledge, this is the first paper demonstrating that
PDE4 inhibitors exert significant inhibitory effects on subchronic cigarette
smoke exposure-induced
lung injury in guinea pigs.