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Roflumilast, a phosphodiesterase 4 inhibitor, alleviates bleomycin-induced lung injury.
Br J Pharmacol 2009; 156(3):534-44BJ

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.

Authors+Show Affiliations

Department of Pharmacology, University of Valencia, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19154443

Citation

Cortijo, J, et al. "Roflumilast, a Phosphodiesterase 4 Inhibitor, Alleviates Bleomycin-induced Lung Injury." British Journal of Pharmacology, vol. 156, no. 3, 2009, pp. 534-44.
Cortijo J, Iranzo A, Milara X, et al. Roflumilast, a phosphodiesterase 4 inhibitor, alleviates bleomycin-induced lung injury. Br J Pharmacol. 2009;156(3):534-44.
Cortijo, J., Iranzo, A., Milara, X., Mata, M., Cerdá-Nicolás, M., Ruiz-Saurí, A., ... Morcillo, E. J. (2009). Roflumilast, a phosphodiesterase 4 inhibitor, alleviates bleomycin-induced lung injury. British Journal of Pharmacology, 156(3), pp. 534-44. doi:10.1111/j.1476-5381.2008.00041.x.
Cortijo J, et al. Roflumilast, a Phosphodiesterase 4 Inhibitor, Alleviates Bleomycin-induced Lung Injury. Br J Pharmacol. 2009;156(3):534-44. PubMed PMID: 19154443.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Roflumilast, a phosphodiesterase 4 inhibitor, alleviates bleomycin-induced lung injury. AU - Cortijo,J, AU - Iranzo,A, AU - Milara,X, AU - Mata,M, AU - Cerdá-Nicolás,M, AU - Ruiz-Saurí,A, AU - Tenor,H, AU - Hatzelmann,A, AU - Morcillo,E J, PY - 2009/1/22/entrez PY - 2009/1/22/pubmed PY - 2009/5/9/medline SP - 534 EP - 44 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 156 IS - 3 N2 - 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/19154443/Roflumilast_a_phosphodiesterase_4_inhibitor_alleviates_bleomycin_induced_lung_injury_ L2 - https://doi.org/10.1111/j.1476-5381.2008.00041.x DB - PRIME DP - Unbound Medicine ER -