Effects of dabigatran on bleomycin‐induced pulmonary toxicities and its safety profile in mice

Abstract

Chronic inflammation causes pulmonary fibrosis. Bleomycin‐induced murine pulmonary toxicity is generally used as a model of interstitial lung disease (ILD). Thrombin is involved in the initial phase of ILD. This study investigated the benefits of dabigatran, a direct thrombin inhibitor on bleomycin‐induced pulmonary changes and its safety profile on hemostasis. Male ICR mice were divided into 3 groups, i.e. saline, bleomycin (50 mg/kg, i.v. in two divided doses on day 1) and dabigatran (bleomycin‐pretreated mice, received 10 mg/kg/day dabigatran etexilate, orally on days 2–9). Tail vein bleeding time was measured on day 10 just before euthanatization. The drug effects on the lung were assessed by the lung coefficient for edema and histological score for inflammation and fibrosis. The results indicated that bleomycin caused lung injuries with significant increases (p<0.05) in all the parameters tested. Dabigatran treatment caused a significant decrease in edema but not in inflammation and fibrosis, while tail vein bleeding time was significantly increased at the dose. Dabigatran at the dosage mentioned had a limited benefit on bleomycin‐induced pulmonary toxicities in mice with bleeding risk. Therefore, for an effective management, dose of dabigatran cannot be increased and may require drug combinations. The authors wish to thank the Thailand International Development Co‐operation Agency for the financial support.