title: Effect of the oral thrombin inhibitor dabigatran on allergic lung inflammation induced by repeated house dust mite administration in mice.
abstract: 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.
authors: Academic Medical Center, University of Amsterdam, Center of Infection and Immunity Amsterdam & Center for Experimental and Molecular Medicine, the Netherlands. j.d.deboer@amc.uva.nl.
authors: Johannes D
authors: JD
authors: de Boer
authors: Academic Medical Center, University of Amsterdam, Center of Infection and Immunity Amsterdam & Center for Experimental and Molecular Medicine, the Netherlands.
authors: Lea C
authors: LC
authors: Berkhout
authors: Academic Medical Center, University of Amsterdam, Center of Infection and Immunity Amsterdam & Center for Experimental and Molecular Medicine, the Netherlands.
authors: Sacha F
authors: SF
authors: de Stoppelaar
authors: Academic Medical Center, University of Amsterdam, Center of Infection and Immunity Amsterdam & Center for Experimental and Molecular Medicine, the Netherlands.
authors: Jack
authors: J
authors: Yang
authors: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors: Roelof
authors: R
authors: Ottenhoff
authors: Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands Department of Plasma Proteins, Sanquin Research, Amsterdam, the Netherlands.
authors: Joost C M
authors: JC
authors: Meijers
authors: Department of Pathology, Academic Medical Center, University of Amsterdam, the Netherlands.
authors: Joris J T H
authors: JJ
authors: Roelofs
authors: Academic Medical Center, University of Amsterdam, Center of Infection and Immunity Amsterdam & Center for Experimental and Molecular Medicine, the Netherlands.
authors: Cornelis
authors: C
authors: van't Veer
authors: Academic Medical Center, University of Amsterdam, Center of Infection and Immunity Amsterdam & Center for Experimental and Molecular Medicine, the Netherlands. Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, the Netherlands.
authors: Tom
authors: T
authors: van der Poll
mesh_terms: D000284:Administration, Oral; D000485:Allergens / Q000008:administration & dosage*; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000008:administration & dosage*; D000990:Antithrombin III / Q000378:metabolism; D000991:Antithrombins / Q000008:administration & dosage; D001249:Asthma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D001777:Blood Coagulation / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D000069604:Dabigatran / Q000008:administration & dosage*; D040002:Dermatophagoides pteronyssinus / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010447:Peptide Hydrolases / Q000378:metabolism
chemical_list: D000485:Allergens; D039741:Antigens, Dermatophagoides; D000991:Antithrombins; D005338:Fibrin Fibrinogen Degradation Products; D018836:Inflammation Mediators; C046193:antithrombin III-protease complex; C036309:fibrin fragment D; D000990:Antithrombin III; D010447:Peptide Hydrolases; D000069604:Dabigatran
keywords: asthma; dabigatran; house dust mite; thrombin