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• W3204082132 abstract "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." @default.
• W3204082132 created "2021-10-11" @default.
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• W3204082132 date "2021-09-24" @default.
• W3204082132 modified "2023-09-26" @default.
• W3204082132 title "<i>In vitro</i> and <i>in vivo</i> modulation of NADPH oxidase activity and reactive oxygen species production in human neutrophils by α₁-antitrypsin" @default.
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• W3204082132 doi "https://doi.org/10.1183/23120541.00234-2021" @default.
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