title: Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice.
abstract: Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related death. The biologic processes contributing to TRALI are poorly understood. All blood products can cause TRALI, and no specific treatment is available. A "2-event model" has been proposed as the trigger. The first event may include surgery, trauma, or infection; the second involves the transfusion of antileukocyte antibodies or bioactive lipids within the blood product. Together, these events induce neutrophil activation in the lungs, causing endothelial damage and capillary leakage. Neutrophils, in response to pathogens or under stress, can release their chromatin coated with granule contents, thus forming neutrophil extracellular traps (NETs). Although protective against infection, these NETs are injurious to tissue. Here we show that NET biomarkers are present in TRALI patients' blood and that NETs are produced in vitro by primed human neutrophils when challenged with anti-HNA-3a antibodies previously implicated in TRALI. NETs are found in alveoli of mice experiencing antibody-mediated TRALI. DNase 1 inhalation prevents their alveolar accumulation and improves arterial oxygen saturation even when administered 90 minutes after TRALI onset. We suggest that NETs form in the lungs during TRALI, contribute to the disease process, and thus could be targeted to prevent or treat TRALI.
authors.affiliation: Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Grace M
authors.initials: GM
authors.lastname: Thomas
authors.forename: Carla
authors.initials: C
authors.lastname: Carbo
authors.forename: Brian R
authors.initials: BR
authors.lastname: Curtis
authors.forename: Kimberly
authors.initials: K
authors.lastname: Martinod
authors.forename: Irina B
authors.initials: IB
authors.lastname: Mazo
authors.forename: Daphne
authors.initials: D
authors.lastname: Schatzberg
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Cifuni
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Fuchs
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
authors.forename: John H
authors.initials: JH
authors.lastname: Hartwig
authors.forename: Richard H
authors.initials: RH
authors.lastname: Aster
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000276:immunology; D000818:Animals; D001782:Blood Donors; D002478:Cells, Cultured; D004247:DNA / Q000276:immunology* / Q000378:metabolism*; D005110:Extracellular Space / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D065227:Transfusion Reaction; D014181:Transplantation Immunology; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D004247:DNA