Phosphodiesterase 4 (PDE4)
isozyme plays important roles in inflammatory and immunomodulatory cells. In this study,
piclamilast, a selective
PDE4 inhibitor, was used to investigate the role of PDE4 in respiratory function and
inflammation in a murine
asthma model. Sensitized mice were challenged with aerosolized
ovalbumin for 7 days,
piclamilast (1, 3 and 10 mg/kg) and
dexamethasone (2 mg/kg) were orally administered once daily during the period of challenge. Twenty-four hours after the last challenge,
airway hyperresponsiveness to
methacholine was determined by whole-body plethysmography, airway
inflammation and mucus secretion by histomorphometry, pulmonary cAMP-PDE activity by HPLC,
cytokine levels in bronchoalveolar lavage fluid and their
mRNA expression in lung by ELISA and RT-PCR, respectively. In control mice, significant induction of cAMP-PDE activity was parallel to the increases of hyperresponsiveness, inflammatory cells,
cytokine levels,
mRNA expression as well as goblet cell
hyperplasia. However,
piclamilast dose-dependently and significantly improved airway resistance and dynamic compliance, and the maximal effect was similar to that of
dexamethasone.
Piclamilast treatment dose-dependently and significantly prevented the increase in inflammatory cell number and goblet cell
hyperplasia, as well as production of
cytokines, including eotaxin,
TNFalpha and
IL-4.
Piclamilast exerted a weaker inhibitory effect than
dexamethasone on eosinophils and neutrophils, had no effect on lymphocyte accumulation. Moreover,
piclamilast inhibited up-regulation of cAMP-PDE activity and
cytokine mRNA expression; the maximal inhibition of cAMP-PDE was greater than that exerted by
dexamethasone, and was similar to
dexamethasone on
cytokine mRNA expression. This study suggests that inhibition of PDE4 by
piclamilast robustly improves the pulmonary function, airway
inflammation and goblet cell
hyperplasia in murine allergenic
asthma.