Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 156, Issue 3, Pages 534-544Publisher
WILEY
DOI: 10.1111/j.1476-5381.2008.00041.x
Keywords
Roflumilast; phosphodiesterase 4 inhibition; bleomycin; pulmonary fibrosis; steroids
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Funding
- CICYT [SAF2005-00669, SAF2006-01002]
- CIBERES (Ministry of Science and Innovation and Health Institute 'Carlos III', Spanish Government) [CB06/06/0027]
- Regional Government ('Generalitat Valenciana')
- Nycomed GmbH (Konstanz, Germany)
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The effects of a phosphodiesterase 4 (PDE4) inhibitor, roflumilast, on bleomycin-induced lung injury were explored in 'preventive' and 'therapeutic' protocols and compared with glucocorticoids. Roflumilast (1 and 5 mg.kg(-1).d(-1), p.o.) or dexamethasone (2.5 mg.kg(-1).d(-1), p.o.) was given to C57Bl/6J mice from day 1 to 14 (preventive) or day 7 to 21 (therapeutic) after intratracheal bleomycin (3.75 U.kg(-1)). In Wistar rats, roflumilast (1 mg.kg(-1).d(-1), p.o.) was compared with methylprednisolone (10 mg.kg(-1).d(-1), p.o.) from day 1 to 21 (preventive) or from day 10 to 21 (therapeutic), following intratracheal instillation of bleomycin (7.5 U.kg(-1)). Analyses were performed at the end of the treatment periods. Preventive. Roflumilast reduced bleomycin-induced lung hydroxyproline, lung fibrosis and right ventricular hypertrophy; muscularization of intraacinar pulmonary vessels was also attenuated. The PDE4 inhibitor diminished bleomycin-induced transcripts for tumour necrosis factor (TNF alpha), transforming growth factor (TGF beta), connective tissue growth factor, alpha I(I)collagen, endothelin-1 and the mucin, Muc5ac, in lung, and reduced bronchoalveolar lavage fluid levels of TNF alpha, interleukin-13, TGF beta, Muc5ac, lipid hydroperoxides and inflammatory cell counts. Therapeutic. In mice, roflumilast but not dexamethasone reduced bleomycin-induced lung alpha I(I)collagen transcripts, fibrosis and right ventricular hypertrophy. Similar results were found in the rat. Roflumilast prevented the development of bleomycin-induced lung injury, and alleviated the lung fibrotic and vascular remodeling response to bleomycin in a therapeutic protocol, the latter being resistant to glucocorticoids.
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