RNA-seq of mouse lung tissue from amiodarone and/or dabigatran treated animals

Interstitial lung disease (ILD) is a group of respiratory disorders characterized by chronic inflammation and fibrosis of the pulmonary interstitial tissues. Although the etiology of ILD remains unclear, some drug treatments are one of the primary causes of ILD. In the present study, we analyzed FDA Adverse Event Reporting System and JMDC insurance claims to find a coexisting drug that reduced the incidence of ILD associated with use of an anti-arrhythmic agent, amiodarone, and found that the thrombin inhibitor dabigatran prevented the amiodarone-induced ILD in both clinical datasets. In an experimental validation of the hypothesis, a long-term, oral treatment of mice with amiodarone caused a gradual decrease in the body weight caused by respiratory insufficiency. In the lung of amiodarone-treated mice, infiltration of macrophages and interstitial thickening were observed in parallel with a delayed upregulation of platelet-derived growth factor receptor α gene. In contrast, co-treatment with dabigatran significantly attenuated these amiodarone-induced changes representing ILD. These results suggest that dabigatran is effective in preventing the drug-induced ILD. This combinatorial approach of drug repositioning based on clinical big data will pave the way for finding a new treatment with high clinical predictability and a well-defined molecular mechanism. Lung mRNA profiles of vehicle-, amiodarone-, dabigatran-, or amiodarone+dabigatran-treated mice.