Roflumilast, a phosphodiesterase 4 inhibitor, alleviates bleomycin-induced lung injury
Version of Record online: 19 JAN 2009
© 2009 The Authors. Journal compilation © 2009 The British Pharmacological Society
British Journal of Pharmacology
Volume 156, Issue 3, pages 534–544, February 2009
How to Cite
Cortijo, J., Iranzo, A., Milara, X., Mata, M., Cerdá-Nicolás, M., Ruiz-Saurí, A., Tenor, H., Hatzelmann, A. and Morcillo, E. (2009), Roflumilast, a phosphodiesterase 4 inhibitor, alleviates bleomycin-induced lung injury. British Journal of Pharmacology, 156: 534–544. doi: 10.1111/j.1476-5381.2008.00041.x
- Issue online: 17 FEB 2009
- Version of Record online: 19 JAN 2009
- Received 1 August 2008; accepted 5 September 2008
- phosphodiesterase 4 inhibition;
- pulmonary fibrosis;
Mandarin translation of abstract
Background and purpose: 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.
Experimental approach: 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.
Key results: 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 (TNFα), transforming growth factor (TGFβ), connective tissue growth factor, αI(I)collagen, endothelin-1 and the mucin, Muc5ac, in lung, and reduced bronchoalveolar lavage fluid levels of TNFα, interleukin-13, TGFβ, Muc5ac, lipid hydroperoxides and inflammatory cell counts. Therapeutic. In mice, roflumilast but not dexamethasone reduced bleomycin-induced lung αI(I)collagen transcripts, fibrosis and right ventricular hypertrophy. Similar results were found in the rat.
Conclusions and implications: 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.