Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke

Am J Respir Crit Care Med. 2005 Oct 1;172(7):848-53. doi: 10.1164/rccm.200411-1549OC. Epub 2005 Jun 16.


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.

MeSH terms

  • Administration, Oral
  • Aminopyridines / administration & dosage
  • Aminopyridines / pharmacology*
  • Aminopyridines / therapeutic use
  • Animals
  • Benzamides / administration & dosage
  • Benzamides / pharmacology*
  • Benzamides / therapeutic use
  • Bronchoalveolar Lavage Fluid / chemistry
  • Cyclopropanes / administration & dosage
  • Cyclopropanes / pharmacology
  • Cyclopropanes / 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
  • Phosphodiesterase Inhibitors / pharmacology*
  • Phosphodiesterase Inhibitors / therapeutic use
  • Pulmonary Emphysema / etiology
  • Pulmonary Emphysema / prevention & control*
  • Smoking / adverse effects*


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