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

Br J Pharmacol. 2009 Feb;156(3):534-44. doi: 10.1111/j.1476-5381.2008.00041.x.

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 (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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / pharmacology
  • Aminopyridines / therapeutic use*
  • Animals
  • Benzamides / pharmacology
  • Benzamides / therapeutic use*
  • Bleomycin / toxicity*
  • Bronchoalveolar Lavage
  • Bronchoalveolar Lavage Fluid / cytology
  • Cyclopropanes / pharmacology
  • Cyclopropanes / therapeutic use
  • Disease Models, Animal
  • Lung / drug effects
  • Lung / enzymology
  • Lung / pathology
  • Lung Injury / chemically induced
  • Lung Injury / enzymology
  • Lung Injury / pathology
  • Lung Injury / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphodiesterase 4 Inhibitors*
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphodiesterase Inhibitors / therapeutic use*
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / enzymology
  • Pulmonary Fibrosis / pathology
  • Pulmonary Fibrosis / prevention & control*
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Aminopyridines
  • Benzamides
  • Cyclopropanes
  • Phosphodiesterase 4 Inhibitors
  • Phosphodiesterase Inhibitors
  • Roflumilast
  • Bleomycin