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.
References
Feb 15, 1990·The Biochemical Journal·S DhoC R Pace-Asciak
Sep 28, 1990·Biochemical and Biophysical Research Communications·S NigamC R Pace-Asciak
Nov 1, 1984·Prostaglandins, Leukotrienes, and Medicine·C R Pace-Asciak, J M Martin
Apr 1, 1999·FEBS Letters·D ReynaudC R Pace-Asciak
Mar 6, 2004·Science·Volker BrinkmannArturo Zychlinsky
Oct 21, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Bryan P HurleyBeth A McCormick
May 24, 2005·Infection and Immunity·Travis S WalkerJerry A Nick
Jul 5, 2007·The FEBS Journal·Beth A McCormick
Mar 11, 2009·Journal of Medical Microbiology·Quinn M ParksJerry A Nick
May 9, 2009·British Journal of Pharmacology·Cecil R Pace-Asciak
Oct 21, 2010·Physiological Reviews·Henrike BerkefeldUwe Schulte
Nov 26, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Florian H PilsczekPaul Kubes
May 27, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·Eneida VillanuevaMariana J Kaplan
Jun 28, 2011·The American Journal of Pathology·Teluguakula NarasarajuVincent T Chow
Mar 6, 2012·PloS One·Mona SaffarzadehKlaus T Preissner
May 19, 2012·Blood·Grace M ThomasDenisa D Wagner
Jun 12, 2012·The Journal of Clinical Investigation·Axelle CaudrillierMark R Looney
Jul 18, 2012·Journal of Leukocyte Biology·Heather ParkerChristine C Winterbourn
Sep 5, 2012·The Journal of Cell Biology·Volker Brinkmann, Arturo Zychlinsky
Oct 10, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·David L TamangBryan P Hurley
Jan 29, 2013·Frontiers in Immunology·Olivia Z Cheng, Nades Palaniyar
Feb 9, 2013·PloS One·Ruth B ThorntonPeter C Richmond
Jul 5, 2013·The Journal of Experimental Medicine·Attila Mócsai
Dec 18, 2013·Blood·Jan RossaintAlexander Zarbock
May 28, 2014·Journal of Innate Immunity·Markryan DwyerMihaela Gadjeva
Sep 15, 2014·Nature Immunology·Nora BranzkVenizelos Papayannopoulos
Citations
May 6, 2016·Frontiers in Immunology·Joshua YuenChristoph Licht
Apr 20, 2016·Nature Communications·Gajanan D KatkarKempaiah Kemparaju
Aug 31, 2016·Frontiers in Immunology·Bárbara Nery Porto, Renato Tetelbom Stein
Nov 5, 2016·Scientific Reports·Manjunath B JoshiKapaettu Satyamoorthy
Feb 9, 2017·Scientific Reports·Meraj A Khan, Nades Palaniyar
Nov 11, 2017·Frontiers in Immunology·Ljubomir VitkovMatthias Hannig
Mar 1, 2019·Genes·Meraj A KhanNades Palaniyar
Sep 22, 2019·Scientific Reports·Diogo N de OliveiraRodrigo R Catharino
Nov 16, 2018·Biomolecules·Meraj A KhanNades Palaniyar
Jan 11, 2021·Clinical Pharmacology and Therapeutics·Lael M YonkerBryan P Hurley
Oct 9, 2020·The Journal of Pain : Official Journal of the American Pain Society·Anthony F DomenichielloChristopher E Ramsden
Jan 30, 2018·ACS Chemical Biology·Laura R ParisiG Ekin Atilla-Gokcumen
Sep 2, 2021·Experimental Lung Research·Aline Andrea da CunhaPaulo Márcio Pitrez