Effect of the oral thrombin inhibitor dabigatran on allergic lung inflammation induced by repeated house dust mite administration in mice

Asthma is a chronic disease of the airways; asthma patients are hampered by recurrent symptoms of dyspnoea and wheezing caused by bronchial obstruction. Most asthma patients suffer from chronic allergic lung inflammation triggered by allergens such as house dust mite (HDM). Coagulation activation in...

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Bibliographic Details
Published in:	American journal of physiology. Lung cellular and molecular physiology 2015-10, Vol.309 (8), p.L768-L775
Main Authors:	de Boer, Johannes D, Berkhout, Lea C, de Stoppelaar, Sacha F, Yang, Jack, Ottenhoff, Roelof, Meijers, Joost C M, Roelofs, Joris J T H, van't Veer, Cornelis, van der Poll, Tom
Format:	Article
Language:	eng
Subjects:	Administration, Oral Allergens - administration & dosage Allergies Animals Antigens, Dermatophagoides - administration & dosage Antithrombin III - metabolism Antithrombins - administration & dosage Asthma Asthma - blood Asthma - drug therapy Asthma - pathology Blood Coagulation - drug effects Bronchoalveolar Lavage Fluid - immunology Dabigatran - administration & dosage Dermatophagoides pteronyssinus Dermatophagoides pteronyssinus - immunology Disease Models, Animal Dust Female Fibrin Fibrinogen Degradation Products - metabolism Humans Inflammation Mediators - metabolism Insects Lung - drug effects Lung - metabolism Lung - pathology Male Mice Mice, Inbred C57BL Peptide Hydrolases - metabolism
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Summary:	Asthma is a chronic disease of the airways; asthma patients are hampered by recurrent symptoms of dyspnoea and wheezing caused by bronchial obstruction. Most asthma patients suffer from chronic allergic lung inflammation triggered by allergens such as house dust mite (HDM). Coagulation activation in the pulmonary compartment is currently recognized as a feature of allergic lung inflammation, and data suggest that coagulation proteases further drive inflammatory mechanisms. Here, we tested whether treatment with the oral thrombin inhibitor dabigatran attenuates allergic lung inflammation in a recently developed HDM-based murine asthma model. Mice were fed dabigatran (10 mg/g) or placebo chow during a 3-wk HDM airway exposure model. Dabigatran treatment caused systemic thrombin inhibitory activity corresponding with dabigatran levels reported in human trials. Surprisingly, dabigatran did not lead to inhibition of HDM-evoked coagulation activation in the lung as measured by levels of thrombin-antithrombin complexes and D-dimer. Repeated HDM administration caused an influx of eosinophils and neutrophils into the lungs, mucus production in the airways, and a T helper 2 response, as reflected by a rise in bronchoalveolar IL-4 and IL-5 levels and a systemic rise in IgE and HDM-IgG1. Dabigatran modestly improved HDM-induced lung pathology (P < 0.05) and decreased IL-4 levels (P < 0.01), without influencing other HDM-induced responses. Considering the limited effects of dabigatran in spite of adequate plasma levels, these results argue against clinical evaluation of dabigatran in patients with asthma.
ISSN:	1040-0605 1522-1504