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Phosphodiesterase 4 inhibition reduces lung fibrosis following targeted type II alveolar epithelial cell injury
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Phosphodiesterase 4 inhibition reduces lung fibrosis following targeted type II alveolar epithelial cell injury
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Journal Article
Phosphodiesterase 4 inhibition reduces lung fibrosis following targeted type II alveolar epithelial cell injury
2018
Overview
Fibrosis of the lung constitutes a major clinical challenge and novel therapies are required to alleviate the associated morbidity and mortality. Investigating the antifibrotic efficacy of drugs that are already in clinical practice offers an efficient strategy to identify new therapies. The phosphodiesterase 4 (PDE4) inhibitors, approved for the treatment of chronic obstructive pulmonary disease, harbor therapeutic potential for pulmonary fibrosis by augmenting the activity of endogenous antifibrotic mediators that signal through cyclic AMP. In this study, we tested the efficacy of several PDE4 inhibitors including a novel compound (Compound 1) in a murine model of lung fibrosis that results from a targeted type II alveolar epithelial cell injury. We also compared the antifibrotic activity of PDE4 inhibition to the two therapies that are FDA‐approved for idiopathic pulmonary fibrosis (pirfenidone and nintedanib). We found that both preventative (day 0–21) and therapeutic (day 11–21) dosing regimens of the PDE4 inhibitors significantly ameliorated the weight loss and lung collagen accumulation that are the sequelae of targeted epithelial cell damage. In a therapeutic protocol, the reduction in lung fibrosis with PDE4 inhibitor administration was equivalent to pirfenidone and nintedanib. Treatment with this class of drugs also resulted in a decrease in plasma surfactant protein D concentration, a reduction in the plasma levels of several chemokines implicated in lung fibrosis, and an in vitro inhibition of fibroblast profibrotic gene expression. These results motivate further investigation of PDE4 inhibition as a treatment for patients with fibrotic lung disease. We demonstrate that prophylactic and therapeutic inhibition of phosphodiesterase 4 with several different antagonists reduces lung fibrosis induced by a targeted injury to the type II alveolar epithelium. In conjunction with the reduction in lung collagen content, phosphodiesterase inhibition also reduced serum surfactant protein C levels and the expression of profibrotic genes by lung fibroblasts.
Publisher
John Wiley and Sons Inc
Subject
Alveolar Epithelial Cells - pathology
/ Aminopyridines - therapeutic use
/ Animals
/ Benzamides - administration & dosage
/ Benzamides - therapeutic use
/ cAMP
/ collagen
/ Cyclopropanes - therapeutic use
/ Dose-Response Relationship, Drug
/ Drug Evaluation, Preclinical - methods
/ Humans
/ Isoquinolines - administration & dosage
/ Isoquinolines - therapeutic use
/ Lung
/ Phosphodiesterase 4 Inhibitors - administration & dosage
/ Phosphodiesterase 4 Inhibitors - blood
/ Phosphodiesterase 4 Inhibitors - therapeutic use
/ Pulmonary Fibrosis - drug therapy
/ Pulmonary Fibrosis - prevention & control
/ Pulmonary Surfactant-Associated Protein D - blood
