title: Activated protein C inhibits neutrophil migration in allergic asthma: a randomised trial.
abstract: Asthma patients show evidence of a procoagulant state in their airways, accompanied by an impaired function of the anticoagulant protein C system. We aimed to study the effect of recombinant human activated protein C (rhAPC) in allergic asthma patients.We conducted a randomised, double-blind, placebo-controlled, proof-of-concept study in house dust mite (HDM) allergic asthma patients. Patients were randomised to receive intravenous rhAPC (24 µg·kg(-1)·h(-1); n=12) or placebo (n=12) for 11 h. 4 h after the start of infusion, a first bronchoscopy was performed to challenge one lung segment with saline (control) and a contralateral segment with a combination of HDM extract and lipopolysaccharide (HDM+LPS), thereby mimicking environmental house dust exposure. A second bronchoscopy was conducted 8 h after intrabronchial challenge to obtain bronchoalveolar lavage fluid (BALF).rhAPC did not influence HDM+LPS induced procoagulant changes in the lung. In contrast, rhAPC reduced BALF leukocyte counts by 43% relative to placebo, caused by an inhibitory effect on neutrophil influx (64% reduction), while leaving eosinophil influx unaltered. rhAPC also reduced neutrophil degranulation products in the airways.Intravenous rhAPC attenuates HDM+LPS-induced neutrophil migration and protein release in allergic asthma patients by an effect that does not rely on coagulation inhibition.
authors.affiliation: Center of Infection and Immunity Amsterdam, and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands j.d.deboer@amc.uva.nl.
authors.forename: J Daan
authors.initials: JD
authors.lastname: de Boer
authors.affiliation: Dept of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands These authors contributed equally to this work.
authors.forename: Marieke
authors.initials: M
authors.lastname: Berger
authors.affiliation: Dept of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands These authors contributed equally to this work.
authors.forename: Christof J
authors.initials: CJ
authors.lastname: Majoor
authors.affiliation: Center of Infection and Immunity Amsterdam, and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Liesbeth M
authors.initials: LM
authors.lastname: Kager
authors.affiliation: Dept of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands Dept of Plasma Proteins, Sanquin, Amsterdam, the Netherlands.
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.affiliation: Center of Infection and Immunity Amsterdam, and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Terpstra
authors.affiliation: Dept of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Rienk
authors.initials: R
authors.lastname: Nieuwland
authors.affiliation: Dept of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Anita N
authors.initials: AN
authors.lastname: Boing
authors.affiliation: Dept of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands Dept of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: Lutter
authors.affiliation: Dept of Immunopathology, Sanquin, Amsterdam, the Netherlands.
authors.forename: Diana
authors.initials: D
authors.lastname: Wouters
authors.affiliation: Dept of Immunopathology, Sanquin, Amsterdam, the Netherlands.
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: van Mierlo
authors.affiliation: Dept of Immunopathology, Sanquin, Amsterdam, the Netherlands Dept of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Sacha S
authors.initials: SS
authors.lastname: Zeerleder
authors.affiliation: Dept of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Elisabeth H
authors.initials: EH
authors.lastname: Bel
authors.affiliation: Center of Infection and Immunity Amsterdam, and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Cornelis
authors.initials: C
authors.lastname: van't Veer
authors.affiliation: Center of Infection and Immunity Amsterdam, and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Alex F
authors.initials: AF
authors.lastname: de Vos
authors.affiliation: Dept of Pulmonology, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands.
authors.forename: Jaring S
authors.initials: JS
authors.lastname: van der Zee
authors.affiliation: Center of Infection and Immunity Amsterdam, and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000485:Allergens / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D001999:Bronchoscopy; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D040002:Dermatophagoides pteronyssinus / Q000276:immunology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D011486:Protein C / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012130:Respiratory Hypersensitivity / Q000188:drug therapy* / Q000276:immunology; D014020:Tissue Extracts / Q000276:immunology / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000485:Allergens; D000925:Anticoagulants; D008070:Lipopolysaccharides; D011486:Protein C; D011994:Recombinant Proteins; D014020:Tissue Extracts