Treatment for alpha-1 antitrypsin deficiency (AATD) could deliver additional cellular benefits that modulate other factors in the physiopathology of the disease, according to an experimental study recently published in the American Journal of Respiratory Cell and Molecular Biology.
Alpha-1 antitrypsin (AAT) augmentation therapy demonstrated in vitro antiinflammatory activity by diminishing controlled neutrophil adhesion, as reported by McEnery and colleagues. They analyzed samples of plasma and blood neutrophils from 20 healthy individuals, 30 patients previously diagnosed with AATD, and 6 patients with AATD undergoing once-weekly intravenous AAT augmentation therapy.
The AATD group exhibited inflammatory-induced structural findings such as higher integrin alpha-M, integrin alpha-L, and cytoskeletal adaptor proteins that generated increments in cytosolic calcium levels and membrane proteolysis of caveolin-1, a cholesterol trafficking protein.
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In contrast, the samples from the patients treated with AAT augmentation therapy showed higher cholesterol and caveolin-1 content in membranes, along with lower expression of integrin in neutrophils with a subsequent decrease in its adhesion capacity.
“Observed differences in neutrophil biology in healthy AATD compared to [healthy control] individuals suggests that other genetic/epigenetic as well as environmental factors are important in the development of AATD-related disease however,” the authors said.
The specific mechanism through which the cholesterol content decreases in cell membranes of patients with AATD is thought to involve calpain. This molecule can cleave caveolin-1 and, in turn, produce an abnormal proteome with higher integrin expression that will later translate into augmented neutrophil adhesion capacity.
AAT augmentation therapy is the only specific treatment for AATD to this date. Although its benefits for patients with this disease are already clearly established due to its capacity to slow lung density loss, diminishing neutrophil adhesion could further limit lung tissue destruction and emphysema mediated by this cell.
“These findings support the hypothesis that AATD is an inflammatory condition and that disease manifestations are not a consequence of protease/anti-protease imbalance alone,” the authors concluded.
McEnery T, White M, Gogoi D, et al. Alpha-1 antitrypsin therapy modifies neutrophil adhesion in patients with obstructive lung disease. Am J Respir Cell Mol Biol. Published online May 4, 2022. doi:10.1165/rcmb.2021-0433oc