Alpha-1 antitrypsin augmentation therapy controls neutrophil adhesion in obstructive lung disease patients
Ireland: Research reveals an auxiliary benefit of alpha-1 antitrypsin (AAT) augmentation therapy in patients with obstructive lung disease as evident by controlled neutrophil adhesion and a decrease in circulating inflammation. The study was published in the American Journal of Respiratory Cell and Molecular Biology.
The deficiency of alpha-1 antitrypsin deficiency (AATD) is characterized by neutrophil-dominated inflammation leading to emphysema. The cholesterol-rich neutrophil outer plasma membrane plays an important role in adhesion and subsequent transmigration to underlying tissues. Tom McEnery, Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Dublin Ireland, and colleagues aimed to investigate mechanisms of increased neutrophil adhesion in AATD and whether AAT augmentation therapy abrogates this effect.
The researchers collected plasma and blood neutrophils from 20 healthy controls, 30 AATD patients, and 6 AATD patients after AAT augmentation therapy. Liquid chromatography–tandem mass spectrometry was used to examine neutrophil membrane protein expression. Calcium fluorometric, μ-calpain, and cell adhesion assays were used to assess the effect of once-weekly intravenous AAT augmentation therapy.
The findings of the study were as follows:
- Decreased neutrophil plasma membrane cholesterol content, yet an increased abundance of integrin α-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, leading to significant calcium-dependent μ-calpain activity (3.5-fold change), 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/2 × 107 cells before and after treatment, respectively), with concurrent decreased neutrophil integrin expression and adhesion.
The authors wrote in their conclusion, "our findings demonstrate an auxiliary benefit of AAT augmentation therapy, evident by a decrease in circulating inflammation and controlled neutrophil adhesion."
Reference:
McEnery T, White MM, Gogoi D, Coleman O, Bergin D, Jundi B, Flannery R, Alsaif FAT, Landers SA, Casey M, Dunlea D, Meleady P, McElvaney NG, Reeves EP. Alpha-1 Antitrypsin Therapy Modifies Neutrophil Adhesion in Patients with Obstructive Lung Disease. Am J Respir Cell Mol Biol. 2022 Jul;67(1):76-88.
doi: 10.1165/rcmb.2021-0433OC. PMID: 35507773.
