Inhibition of airway hyperresponsiveness and pulmonary inflammation by roflumilast and other PDE4 inhibitors

Roflumilast is an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor with anti-inflammatory activity. We compared the anti-inflammatory effects of roflumilast with those of PDE4 inhibitors rolipram, piclamilast, and cilomilast in ovalbumin (OVA)-sensitized and challenged Brown-Norway rats. Animals were treated orally 1 h before OVA challenge with roflumilast (0.3, 1.0, and 3.0 mg/kg), rolipram (0.8, 2.8, and 8.3 mg/kg), piclamilast (10.0, 20.0, and 30.0 mg/kg), or cilomilast (10.3, 34.3, and 103.0 mg/kg). Airway hyperresponsiveness (AHR) against adenosine was investigated by measuring airway resistance 200 min after OVA challenge. Subsequently, neutrophil influx and tumor necrosis factor-alpha (TNF-α) release in the lungs were determined by bronchoalveolar lavage. Direct bronchodilation at the time point of AHR assessment by PDE4 inhibitors was examined in serotonin-challenged animals. Evaluation of neutropenic animals or treatment with anti-TNF-α antibody revealed that AHR was independent of neutrophil accumulation or TNF-α release. Roflumilast (50% inhibitory dose [ID50]=1.5 mg/kg) inhibited AHR 3-, 16-, and 27-fold more potently than rolipram, piclamilast, and cilomilast, respectively. Likewise, roflumilast was a more potent inhibitor of neutrophil influx (ID50=0.9 mg/kg) than rolipram (ID50=6.9 mg/kg), piclamilast (ID50=28.1 mg/kg), or cilomilast (ID50=37.7 mg/kg). Roflumilast, rolipram, and piclamilast—but not cilomilast—suppressed OVA-induced TNF-α release in a dose-dependent manner. Roflumilast (ID50=0.9 mg/kg) exhibited 9- and 23-fold more potent inhibition of TNF-α release than rolipram and piclamilast, respectively. Roflumilast did not inhibit serotonin-induced bronchoconstriction 4.5 h after administration, suggesting that inhibition of AHR by roflumilast results from anti-inflammatory, not bronchodilatory, effects. This study suggests that roflumilast has anti-inflammatory action and provides rationale for the investigation of roflumilast in asthmatic patients.