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- Title
Alpha-1 Antitrypsin Therapy Modifies Neutrophil Adhesion in Patients with Obstructive Lung Disease.
- Authors
McEnery, Tom; White, Michelle M.; Gogoi, Debananda; Coleman, Orla; Bergin, David; Jundi, Bakr; Flannery, Ryan; T. Alsaif, Fatima Abbas; Landers, Sarah A.; Casey, Michelle; Dunlea, Danielle; Meleady, Paula; McElvaney, Noel G.; Reeves, Emer P.
- Abstract
Alpha-1 antitrypsin deficiency (AATD) is characterized by neutrophil-dominated inflammation resulting in emphysema. The cholesterol-rich neutrophil outer plasma membrane plays a central role in adhesion and subsequent transmigration to underlying tissues. This study aimed to investigate mechanisms of increased neutrophil adhesion in AATD and whether alpha-1 antitrypsin (AAT) augmentation therapy abrogates this effect. Plasma and blood neutrophils were donated by healthy controls (n = 20), AATD (n = 30), and AATD patients after AAT augmentation therapy (n = 6). Neutrophil membrane protein expression was investigated using liquid chromatography–tandem mass spectrometry. The effect of once-weekly intravenous AAT augmentation therapy was assessed by calcium fluorometric, μ-calpain, and cell adhesion assays. Decreased neutrophil plasma membrane cholesterol content (P = 0.03), yet increased abundance of integrin a-M (fold change 1.91), integrin α-L (fold change 3.76), and cytoskeletal adaptor proteins including talin-1 (fold change 4.04) were detected on AATD neutrophil plasma membrane fractions. The described inflammatory induced structural changes were a result of a more than twofold increased cytosolic calcium concentration (P = 0.02), leading to significant calcium-dependent μ-calpain activity (3.5-fold change; P = 0.005), resulting in proteolysis of the membrane cholesterol trafficking protein caveolin-1. Treatment of AAT-deficient individuals with AAT augmentation therapy resulted in increased caveolin-1 and membrane cholesterol content (111.8 ± 15.5 vs. 64.18± 7.8 μg/2x 107 cells before and after treatment, respectively; P = 0.02), with concurrent decreased neutrophil integrin expression and adhesion. Results demonstrate an auxiliary benefit of AAT augmentation therapy, evident by a decrease in circulating inflammation and controlled neutrophil adhesion.
- Subjects
CALPAIN; OBSTRUCTIVE lung diseases; LIQUID chromatography-mass spectrometry; NEUTROPHILS; TRYPSIN inhibitors; BLOOD plasma; LUNGS
- Publication
American Journal of Respiratory Cell & Molecular Biology, 2022, Vol 67, Issue 1, p76
- ISSN
1044-1549
- Publication type
Article
- DOI
10.1165/rcmb.2021-0433OC