Roflumilast fully prevents emphysema in mice chronically exposed to cigarette smoke.
BACKGROUND
There is a need for new agents capable of suppressing the inflammatory response in chronic obstructive pulmonary disease.


OBJECTIVE
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.


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.
Martorana
Piero A
PA
Department of Physiopathology and Experimental Medicine, University of Siena, Via Aldo Moro 6, I-53100 Siena, Italy. martorana@unisi.it
Beume
Rolf
R
Lucattelli
Monica
M
Wollin
Lutz
L
Lungarella
Giuseppe
G
D000284:Administration, Oral; D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003521:Cyclopropanes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020397:Goblet Cells / Q000473:pathology; D006965:Hyperplasia; D016753:Interleukin-10 / Q000032:analysis; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011656:Pulmonary Emphysema / Q000209:etiology / Q000517:prevention & control*; D012907:Smoking / Q000009:adverse effects*
D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D010726:Phosphodiesterase Inhibitors; C424423:Roflumilast; D016753:Interleukin-10