Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke.

Abstract

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.

• Authors: Piero A Martorana, Rolf Beume, Monica Lucattelli, Lutz Wollin, Giuseppe Lungarella
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 172 Issue 7 Pg. 848-53 (Oct 01 2005) ISSN: 1073-449X [Print] United States
• PMID: 15961691 (Publication Type: Journal Article)

Chemical References

• Aminopyridines
• Benzamides
• Cyclopropanes
• Phosphodiesterase Inhibitors
• Roflumilast
• Interleukin-10

Topics

• Administration, Oral
• Aminopyridines (administration & dosage, pharmacology, therapeutic use)
• Animals
• Benzamides (administration & dosage, pharmacology, therapeutic use)
• Bronchoalveolar Lavage Fluid (chemistry)
• Cyclopropanes (administration & dosage, pharmacology, therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Goblet Cells (pathology)
• Hyperplasia
• Interleukin-10 (analysis)
• Macrophages (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Phosphodiesterase Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Pulmonary Emphysema (etiology, prevention & control)
• Smoking (adverse effects)