The orally active PDE4 inhibitors roflumilast and CDP840, given either as a single dose or regularly are known to inhibit the allergen-induced LAR and AHR [29–31], and rolfumilast has been shown to reduce sputum eosinophil and neutrophils in subjects with COPD . We hypothesized that oral roflumilast would also attenuate allergen-induced airway inflammation, including neutrophilia, which is not generally a target for asthma treatment asthma . This study examined the safety of 14 days' oral treatment with roflumilast 500 mcg in patients with mild asthma and its effects on allergen-induced airway inflammation. The results show that roflumilast attenuated allergen-induced accumulation of inflammatory cells and inflammatory mediators.
In asthma, there is an increase in the number of inflammatory cells within the airways. It is believed that through the release of their mediators and enzymes [4–6] these effector cells contribute to the persistence of inflammation, AHR and increased bronchial tone [1–3]. Roflumilast is a selective PDE4 inhibitor, this inhibition leads to increased cAMP levels in inflammatory cells, rendering them less likely to respond to stimuli. Thus, cell functions, including chemotaxis, survival and activation, which are mediated through cAMP, will be impaired with roflumilast treatment. Roflumilast has been shown to block inflammatory cell influx through inhibition of P- and E-selectin expression on endothelial cells, and CD11b expression on neutrophils , and blocks the release of various inflammatory mediators including TNF-alpha, LTB4, IL-4 and IL-5 . In keeping with the proposed broad anti-inflammatory effects of roflumilast, the allergen-induced increase in eosinophils, neutrophils, MCC and total leukocyte counts in sputum were inhibited with active treatment. This inhibitory effect on inflammatory cell numbers was also observed in the sputum of subjects with COPD where 500 mcg roflumilast once daily for 4 weeks decreased the total cell count .
We hypothesized that roflumilast would suppress the migration and activation of cells involved in the allergic immune response in the airways following allergen inhalation challenge, and thus reduce the physiological responses of EAR, LAR and AHR. This study demonstrates that roflumilast attenuates allergen-induced physiologic responses in subjects with mild allergic asthma, albeit the effect is small as compared to inhaled corticosteroids . Inhibition of physiologic responses is coincident with a larger inhibition of airway inflammation, especially the neutrophil population. Airway neutrophilia has been shown to be elevated in severe asthma, however this could be due, in part, to inhaled corticosteroid treatment . As such, the role of the neutrophil in asthma is still uncertain. Mast cells and basophils are positioned to play a major role in the development of the EAR following IgE-dependent release of histamine and cysteinyl leukotrienes. Inhibition of activation of MCC in sputum by inhaled allergen provides one mechanism for inhibition of the EAR by roflumilast. Likewise, reduced accumulation of eosinophils, neutrophils and their mediators in the airways post allergen reduces inflammatory signals that contribute to development of the LAR. Inhibition of allergen-induced EAR and LAR and AHR is unlikely to be mediated through smooth muscle relaxation because we did not observe improvements in FEV1 post-dosing consistent with the lack of direct bronchodilatory activity .