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Roflumilast Fully Prevents Emphysema in Mice Chronically Exposed to Cigarette Smoke

Department of Physiopathology and Experimental Medicine, University of Siena, Siena, Italy; and ALTANA Pharma, Konstanz, Germany

Correspondence and requests for reprints should be addressed to Prof. Piero A. Martorana, D.V.M., Department of Physiopathology and Experimental Medicine, University of Siena, Via Aldo Moro 6, I-53100 Siena, Italy. E-mail: martorana{at}unisi.it

Rationale: There is a need for new agents capable of suppressing the inflammatory response in chronic obstructive pulmonary disease. Objectives: This study evaluated the effects of roflumilast, a phosphodiesterase 4 (PDE4) inhibitor on acute lung inflammation and chronic lung changes in models of cigarette exposure in mice.

Methods: Roflumilast was given orally either at 1 mg/kg (R1) or at 5 mg/kg (R5). In the acute model (five cigarettes for 20 minutes), bronchoalveolar lavage fluid (BALF) changes were investigated at 4 and 24 hours. In the chronic model (three cigarettes/day for 7 months), morphometric and biochemical parameters were assessed at 7 months.

Measurements and Main Results: Acute exposure caused a fivefold increase in BALF neutrophils. Both doses of roflumilast partially prevented (by 30%) this increase. In addition, after smoke exposure, R1 increased BALF interleukin-10 by 79% and R5 by 129%. Chronic smoke exposure caused a 1.8-fold increase in lung macrophage density, emphysema, an increase of the mean linear intercept (+21%), a decrease of the internal surface area (–13%), and a drop (–13%) in lung desmosine content. R1 did not have any effect, whereas R5 prevented the increase in lung macrophage density by 70% and fully prevented the other changes. In addition, in the smoke-exposure group, 63% of the mice showed goblet cell metaplasia, and neither of the doses of roflumilast had any effect.

Conclusions: This study shows for the first time that a PDE4 inhibitor partially ameliorates lung inflammation and fully prevents parenchymal destruction induced by cigarette smoke.

Key Words: chronic obstructive pulmonary disease • interleukin-10 • lung inflammation