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.
Highlights
Pulmonary fibrotic remodeling is characterized by the development of excess fibrous connective tissue in the lungs
The phosphodiesterase 4 (PDE4) inhibitor roflumilast was administered in a preventive protocol, to measure metabolic changes related with inflammation and fibrosis, which consisted in animals receiving roflumilast once daily, starting from the day of bleomycin administration until the end of the experiment at day 14
In this study we investigated metabolic changes in the murine model of pulmonary fibrotic remodeling secondary to bleomycin and their potential prevention by roflumilast, a PDE4 inhibitor
Summary
Pulmonary fibrotic remodeling is characterized by the development of excess fibrous connective tissue in the lungs. This process is common to lung diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, acute respiratory distress syndrome and asthma among others [1]. A persistent airway inflammation may support fibrotic remodeling in COPD or asthma. In these latter ailments, anti-inflammatory treatment may mitigate a risk of airway fibrotic remodeling. Among the variety of emerging strategies currently in development for diminishing inflammation in respiratory diseases, the inhibition of phosphodiesterase (PDE) 4 has shown promising results [2].
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