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Published ahead of print on June 16, 2005, doi:10.1164/rccm.200411-1549OC

Am. J. Respir. Crit. Care Med., Volume 172, Number 7, October 2005, 848-853

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Submitted on November 19, 2004
Accepted on June 13, 2005

Roflumilast Fully Prevents Emphysema in Mice Chronically Exposed to Cigarette Smoke

Piero A Martorana1*, Rolf Beume2, Monica Lucattelli1, Lutz Wollin2, and Giuseppe Lungarella1

1 Department of Physiopathology and Experimental Medicine, University of Siena, Siena, Italy, 2 ALTANA Pharma, Konstanz, Germany

* To whom correspondence should be addressed. E-mail: Martorana{at}unisi.it ; PHMartorana@compuserve.com.

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 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 (5 cigarettes for 20 min) bronchoalveolar lavage fluid (BALF) changes were investigated at 4 and 24 hours. In the chronic model (3 cigarettes/day for 7 months) morphometrical and biochemical parameters were assessed at 7 months. Measurements and Main Results: Acute exposure caused a 5-fold increase in BALF neutrophils. Both doses of R partially prevented (by 30%) this increase. Additionally, following 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 while R5 prevented the increase in lung macrophage density by 70% and fully prevented the other changes. Additionally, in the smoke group 63% of the mice showed goblet cell metaplasia. Neither doses of R 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: Lung inflammation, COPD, Interleukin-10




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