title: A lipid mediator hepoxilin A3 is a natural inducer of neutrophil extracellular traps in human neutrophils.
abstract: Pulmonary exacerbations in cystic fibrosis airways are accompanied by inflammation, neutrophilia, and mucous thickening. Cystic fibrosis sputum contains a large amount of uncleared DNA contributed by neutrophil extracellular trap (NET) formation from neutrophils. The exact mechanisms of the induction of NETosis in cystic fibrosis airways remain unclear, especially in uninfected lungs of patients with early cystic fibrosis lung disease. Here we show that Hepoxilin A3, a proinflammatory eicosanoid, and the synthetic analog of Hepoxilin B3, PBT-3, directly induce NETosis in human neutrophils. Furthermore, we show that Hepoxilin A3-mediated NETosis is NADPH-oxidase-dependent at lower doses of Hepoxilin A3, while it is NADPH-oxidase-independent at higher doses. Together, these results demonstrate that Hepoxilin A3 is a previously unrecognized inducer of NETosis in cystic fibrosis lungs and may represent a new therapeutic target for treating cystic fibrosis and other inflammatory lung diseases.
authors.affiliation: Lung Innate Immunity Research Laboratory, Program in Physiology & Experimental Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 0A4 ; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada M5G 0A4 ; Pulmonary & Critical Care Medicine Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Douda
authors.affiliation: Lung Innate Immunity Research Laboratory, Program in Physiology & Experimental Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 0A4 ; Division of Respiratory Medicine, Department of Paediatrics, The Hospital for Sick Children, Toronto, ON, Canada M5G 1X8 ; Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Grasemann
authors.affiliation: Lung Innate Immunity Research Laboratory, Program in Physiology & Experimental Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 0A4 ; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Cecil
authors.initials: C
authors.lastname: Pace-Asciak
authors.affiliation: Lung Innate Immunity Research Laboratory, Program in Physiology & Experimental Medicine, The Hospital for Sick Children Research Institute, Toronto, ON, Canada M5G 0A4 ; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada M5G 0A4 ; Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada M5S 1A8.
authors.forename: Nades
authors.identifier: 0000-0002-2170-8548
authors.initials: N
authors.lastname: Palaniyar
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000378:metabolism; D065206:Extracellular Traps / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects*
chemical_list: C022948:10-hydroxy-11,12-epoxyeicosa-5,8,14-trienoic acid; C038243:8-hydroxy-11,12-epoxyeicosa-5,9,14-trienoic acid; D015126:8,11,14-Eicosatrienoic Acid