Rationale: As indicated in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, there is a pressing need to develop new agents capable of suppressing the inflammatory response in chronic obstructive pulmonary disease (COPD). Methods: Since cigarette smoke is the major risk factor for the development of COPD, we investigated the effects of roflumilast, a novel targeted phosphodiesterase 4 (PDE4) inhibitor, given orally either at 1 mg/kg or at 5 mg/kg, in an acute and in a chronic model of cigarette smoke exposure in mice (C57Bl/6J). Control mice were exposed to air. Results: Acute exposure to the smoke of 5 cigarettes resulted in an increase (+404%) of bronchoalveolar lavage fluid (BALF) neutrophils within 24 hours. Both roflumilast doses significantly inhibited (by 37%) this increase. Additionally, roflumilast 1mg/kg and 5 mg/kg increased the levels of the anti-inflammatory cytokine interleukin-10 by 79% (p<0.05) and 129% (0.05), respectively, in BALF. Chronic exposure to cigarette smoke for 7 months resulted in disseminated foci of emphysema mirrored by an increase of the mean linear intercept (+21%, p<0.05), a decrease of the internal surface area (–13%, p<0.05), and a drop (-13%, p<0.05) in lung desmosine content. Roflumilast at a dose of 1 mg/kg did not have any effect, while at 5 mg/kg roflumilast fully prevented the morphological, morphometrical, and the biochemical changes. Conclusions: This is the first study to show that administration of a targeted PDE4 inhibitor ameliorates lung inflammation induced by acute exposure to cigarette smoke and fully prevents elastolytic parenchymal destruction induced by chronic cigarette smoke exposure.

Martorana, P.A., Beume, R., Lucattelli, M., Wollin, L., & Lungarella, G. (2005). Roflumilast, a Targeted Phosphodiesterase 4 Inhibitor, Fully Prevents the Development of Emphysema Induced by Cigarette Smoke Exposure. PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY, 2, A543.

Roflumilast, a Targeted Phosphodiesterase 4 Inhibitor, Fully Prevents the Development of Emphysema Induced by Cigarette Smoke Exposure

LUCATTELLI, MONICA;LUNGARELLA, GIUSEPPE
2005

Abstract

Rationale: As indicated in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, there is a pressing need to develop new agents capable of suppressing the inflammatory response in chronic obstructive pulmonary disease (COPD). Methods: Since cigarette smoke is the major risk factor for the development of COPD, we investigated the effects of roflumilast, a novel targeted phosphodiesterase 4 (PDE4) inhibitor, given orally either at 1 mg/kg or at 5 mg/kg, in an acute and in a chronic model of cigarette smoke exposure in mice (C57Bl/6J). Control mice were exposed to air. Results: Acute exposure to the smoke of 5 cigarettes resulted in an increase (+404%) of bronchoalveolar lavage fluid (BALF) neutrophils within 24 hours. Both roflumilast doses significantly inhibited (by 37%) this increase. Additionally, roflumilast 1mg/kg and 5 mg/kg increased the levels of the anti-inflammatory cytokine interleukin-10 by 79% (p<0.05) and 129% (0.05), respectively, in BALF. Chronic exposure to cigarette smoke for 7 months resulted in disseminated foci of emphysema mirrored by an increase of the mean linear intercept (+21%, p<0.05), a decrease of the internal surface area (–13%, p<0.05), and a drop (-13%, p<0.05) in lung desmosine content. Roflumilast at a dose of 1 mg/kg did not have any effect, while at 5 mg/kg roflumilast fully prevented the morphological, morphometrical, and the biochemical changes. Conclusions: This is the first study to show that administration of a targeted PDE4 inhibitor ameliorates lung inflammation induced by acute exposure to cigarette smoke and fully prevents elastolytic parenchymal destruction induced by chronic cigarette smoke exposure.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11365/44109
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