Inhibition of phosphodiesterase 4 attenuates airway hyperresponsiveness and airway inflammation in a model of secondary allergen challenge

We compared for the first time the therapeutic potential of a specific phos phodiesterase 4 (PDE4) inhibitor, rolipram, with anti-VLA-4 and anti-IL-5 i n a model of secondary allergen exposure of previously sensitized and chall enged mice. To address these issues, mice were sensitized and challenged wi th ovalbumin (OVA) (primary challenge). Six weeks later, sensitized/challen ged mice were reexposed to OVA (secondary challenge) and airway response (r esistance [RL] and dynamic compliance [Cdyn]) to inhaled methacholine was m onitored. After secondary OVA challenge, Rr significantly increased as did the number of lung inflammatory cells and IL-4 and IL-5 production in bronc hoalveolar lavage fluid (BALF). Administration of rolipram, in a dose-depen dent manner, significantly prevented both changes in Rr and Cdyn, as well a s eosinophil, lymphocyte, and neutrophil accumulation in the BALF; IL-4 and IL-5 levels in BALF were also significantly reduced. In contrast, treatmen t with anti-VLA-4 and anti-IL-5 only prevented changes in RL and eosinophil numbers and IL-5 production in BALF. Further, goblet cell hyperplasia was suppressed only by treatment with rolipram. None of the treatments affected OVA-specific antibody levels. These studies confirm that IL-5 dependent eo sinophilic inflammation plays an essential role in the development of certa in aspects of airway function after rechallenge of sensitized mice and that lymphocytes and neutrophils are also important in the development of alter ed airway function. The use of agents that inhibit PDE4 may have an importa nt role in the treatment of asthma in previously sensitized mice.