In vitro and in vivo modulation of NADPH oxidase activity and reactive oxygen species production in human neutrophils by α1-antitrypsin
| العنوان: | In vitro and in vivo modulation of NADPH oxidase activity and reactive oxygen species production in human neutrophils by α1-antitrypsin |
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| المؤلفون: | Vipatsorn Shutchaidat, Michael Henry, Bader Alfawaz, Claudie Gabillard-Lefort, Mark E Murphy, Noel G. McElvaney, Padraig Hawkins, Paula Meleady, Thomas McEnery, Orla Coleman, Emer P. Reeves, David A. Bergin |
| المصدر: | ERJ Open Research, Vol 7, Iss 4 (2021) ERJ Open Research article-version (VoR) Version of Record |
| بيانات النشر: | European Respiratory Society, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Pulmonary and Respiratory Medicine, chemistry.chemical_classification, Reactive oxygen species, Lung Biology, congenital, hereditary, and neonatal diseases and abnormalities, Innate immune system, medicine.diagnostic_test, business.industry, Superoxide, Pharmacology, medicine.disease_cause, Pathogenesis, chemistry.chemical_compound, chemistry, Western blot, In vivo, Original Research Articles, Medicine, business, Ex vivo, Oxidative stress |
| الوصف: | Oxidative stress from innate immune cells is a driving mechanism that underlies COPD pathogenesis. Individuals with α-1 antitrypsin (AAT) deficiency (AATD) have a dramatically increased risk of developing COPD. To understand this further, the aim of this study was to investigate whether AATD presents with altered neutrophil NADPH oxidase activation, due to the specific lack of plasma AAT. Experiments were performed using circulating neutrophils isolated from healthy controls and individuals with AATD. Superoxide anion (O2−) production was determined from the rate of reduction of cytochrome c. Quantification of membrane NADPH oxidase subunits was performed by mass spectrometry and Western blot analysis. The clinical significance of our in vitro findings was assessed in patients with AATD and severe COPD receiving intravenous AAT replacement therapy. In vitro, AAT significantly inhibited O2− production by stimulated neutrophils and suppressed receptor stimulation of cyclic adenosine monophosphate and extracellular signal-regulated kinase (ERK)1/2 phosphorylation. In addition, AAT reduced plasma membrane translocation of cytosolic phox components of the NADPH oxidase. Ex vivo, AATD neutrophils demonstrated increased plasma membrane-associated p67phox and p47phox and significantly increased O2− production. The described variance in phox protein membrane assembly was resolved post-AAT augmentation therapy in vivo, the effects of which significantly reduced AATD neutrophil O2− production to that of healthy control cells. These results expand our knowledge on the mechanism of neutrophil-driven airways disease associated with AATD. Therapeutic AAT augmentation modified neutrophil NADPH oxidase assembly and reactive oxygen species production, with implications for clinical use in conditions in which oxidative stress plays a pathogenic role. Circulating neutrophils in COPD due to α1-antitrypsin deficiency illustrate increased NADPH oxidase assembly and reactive oxygen species production, a defect corrected by α1-antitrypsin augmentation therapy https://bit.ly/38NNTzMTest |
| اللغة: | English |
| تدمد: | 2312-0541 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c4c12b221e483cf6a075ab8311f17278Test http://openres.ersjournals.com/content/7/4/00234-2021.fullTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c4c12b221e483cf6a075ab8311f17278 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23120541 |
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