TY - JOUR T1 - Neutrophil Extracellular Trap Formation is regulated by CXCR2 in COPD neutrophils JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.00970-2017 SP - 1700970 AU - Frauke Pedersen AU - Benjamin Waschki AU - Sebastian Marwitz AU - Torsten Goldmann AU - Anne Kirsten AU - Anna Malmgren AU - Klaus F. Rabe AU - Mohib Uddin AU - Henrik Watz Y1 - 2018/01/01 UR - http://erj.ersjournals.com/content/early/2018/02/15/13993003.00970-2017.abstract N2 - Chronic obstructive pulmonary disease (COPD) is characterized by persistent neutrophilic inflammation of the airways, which is associated with enhanced neutrophil extracellular trap (NET) formation of airway neutrophils (1-3). NETs are web-like extracellular structures consisting of neutrophil DNA components and degradative enzymes (e.g. neutrophil elastase and myeloperoxidase) which are released from azurophilic granules by activated neutrophils (4). Initially found to immunoregulate host defence responses during bacterial infections, emerging data indicate that exaggerated NET formation and/or delayed NET clearance may inflict tissue damage and organ dysfunction in a range of human inflammatory diseases independent of infections (5;6). Recently, we found NET formation of sputum neutrophils and extracellular DNA levels in sputum supernatant to be significantly enhanced in patients with stable COPD irrespective of the current smoking state or the purulence of the sputum samples (1). Several studies, including our own, show that the amount of NET formation and/or level of extracellular DNA in patients with stable COPD correlate with the airflow limitation, suggesting that NET formation by airway neutrophils may contribute to the lung tissue damage observed in COPD (1-3). However, the underlying mechanisms inducing NET formation in COPD neutrophils are largely unexplored. Furthermore, it is unknown whether neutrophils undergo NETosis following migration into the lung tissues or whether neutrophils are constitutively poised to undergo this response in circulation during COPD-related inflammation. It is notable that there is an increase in the release of cell-free DNA and myeloperoxidase that are active constituents of NETs in peripheral blood in COPD patients (7-9). Here, we aimed to compare NET formation in autologous neutrophils derived from peripheral blood and sputum from COPD patients ex vivo. We also investigated whether the selective CXCR2 antagonist AZD5069, that has been shown to block trafficking of neutrophils from blood into airways in bronchiectasis patients (10) and more recently in a small cohort of neutrophilic asthma patients (11) could dampen NET formation in COPD-derived neutrophils ex vivo.CXCR2 might have a crucial role in NET formation in COPD neutrophilsFootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Pedersen reports grants from AstraZeneca, during the conduct of the study.Conflict of interest: Dr. Waschki reports grants from AstraZeneca, during the conduct of the study.Conflict of interest: Dr. Marwitz has nothing to disclose.Conflict of interest: Dr. Goldmann has nothing to disclose.Conflict of interest: Dr. Kirsten reports grants from AstraZeneca, during the conduct of the study; personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, outside the submitted work.Conflict of interest: Dr. Malmgren reports other from AstraZeneca, during the conduct of the study.Conflict of interest: Dr. Rabe reports other from AstraZeneca, during the conduct of the study; personal fees from AstraZeneca, personal fees from BerlinChemie, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from Novartis, personal fees from SanofiAventis, personal fees from Teva, outside the submitted work.Conflict of interest: Dr. Uddin reports other from AstraZeneca, during the conduct of the study.Conflict of interest: Dr. Watz reports grants from AstraZeneca, during the conduct of the study; personal fees and non-financial support from AstraZeneca, personal fees from BerlinChemie, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees and non-financial support from GlaxoSmithKline, personal fees and non-financial support from Novartis, from null, outside the submitted work. ER -