title: Roflumilast Prevents the Metabolic Effects of Bleomycin-Induced Fibrosis in a Murine Model.
abstract: Fibrotic remodeling is a process common to chronic lung diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, acute respiratory distress syndrome and asthma. Based on preclinical studies phosphodiesterase 4 (PDE4) inhibitors may exhibit beneficial anti-inflammatory and anti-remodeling properties for the treatment of these respiratory disorders. Effects of PDE4 inhibitors on changes in the lung metabolome in models of pulmonary fibrotic remodeling have not yet been explored. This work studies the effects of the PDE4 inhibitor roflumilast on changes in the lung metabolome in the common murine model of bleomycin-induced lung fibrosis by nuclear magnetic resonance (NMR) metabolic profiling of intact lung tissue. Metabolic profiling reveals strong differences between fibrotic and non-fibrotic tissue. These differences include increases in proline, glycine, lactate, taurine, phosphocholine and total glutathione and decreases in global fatty acids. In parallel, there was a loss in plasma BH4. This profile suggests that bleomycin produces alterations in the oxidative equilibrium, a strong inflammatory response and activation of the collagen synthesis among others. Roflumilast prevented most of these metabolic effects associated to pulmonary fibrosis suggesting a favorable anti-fibrotic profile.
authors.affiliation: Clinical Research Unit, University General Hospital Consortium, Valencia, Spain; CIBERES, Health Institute Carlos III, Valencia, Spain; Research Foundation of General Hospital of Valencia, Av. tres cruces s/n., E-46014, Valencia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Milara
authors.affiliation: CIBERES, Health Institute Carlos III, Valencia, Spain; Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain.
authors.forename: Esteban
authors.initials: E
authors.lastname: Morcillo
authors.affiliation: Fundacion Investigacion Hospital Clinico Universitario/INCLIVA, Valencia, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Monleon
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain.
authors.forename: Herman
authors.initials: H
authors.lastname: Tenor
authors.affiliation: Clinical Research Unit, University General Hospital Consortium, Valencia, Spain; CIBERES, Health Institute Carlos III, Valencia, Spain; Research Foundation of General Hospital of Valencia, Av. tres cruces s/n., E-46014, Valencia, Spain; Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Cortijo
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001761:Bleomycin; D003521:Cyclopropanes / Q000494:pharmacology; D004195:Disease Models, Animal; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D003521:Cyclopropanes; C424423:Roflumilast; D001761:Bleomycin