Roflumilast Fully Prevents Emphysema in Mice Chronically Exposed to Cigarette Smoke

作者：Piero A. Martorana, Rolf Beume, Monica Lucattelli, Lutz Wollin, Giuseppe Lungarella · 发表于：American Journal of Respiratory and Critical Care Medicine · 年份：2005 · DOI：10.1164/rccm.200411-1549oc · 被引用次数：194 · 研究领域：Phosphodiesterase function and regulation、Chronic Obstructive Pulmonary Disease (COPD) Research、Adenosine and Purinergic Signaling

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 inhibit...