title: Roflumilast, a phosphodiesterase 4 inhibitor, alleviates bleomycin-induced lung injury.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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 (TNFalpha), transforming growth factor (TGFbeta), connective tissue growth factor, alphaI(I)collagen, endothelin-1 and the mucin, Muc5ac, in lung, and reduced bronchoalveolar lavage fluid levels of TNFalpha, interleukin-13, TGFbeta, Muc5ac, lipid hydroperoxides and inflammatory cell counts. Therapeutic. In mice, roflumilast but not dexamethasone reduced bleomycin-induced lung alphaI(I)collagen transcripts, fibrosis and right ventricular hypertrophy. Similar results were found in the rat.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology, University of Valencia, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Cortijo
authors.forename: A
authors.initials: A
authors.lastname: Iranzo
authors.forename: X
authors.initials: X
authors.lastname: Milara
authors.forename: M
authors.initials: M
authors.lastname: Mata
authors.forename: M
authors.initials: M
authors.lastname: Cerdá-Nicolás
authors.forename: A
authors.initials: A
authors.lastname: Ruiz-Saurí
authors.forename: H
authors.initials: H
authors.lastname: Tenor
authors.forename: A
authors.initials: A
authors.lastname: Hatzelmann
authors.forename: E J
authors.initials: EJ
authors.lastname: Morcillo
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D001761:Bleomycin / Q000633:toxicity*; D018893:Bronchoalveolar Lavage; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003521:Cyclopropanes / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; C424423:Roflumilast; D001761:Bleomycin