Roflumilast, a phosphodiesterase 4 inhibitor, alleviates bleomycin-induced lung injury

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. © 2009 The British Pharmacological Society.