Augmentation therapy with alpha-1 antitrypsin (AAT) protein may help reduce levels of reactive oxygen species (ROS) including superoxide (O2-) in patients with AAT deficiency (AATD). The results are part of an in vitro and ex vivo study published in ERJ Open Research.
The study showed that AAT modulates the binding of formylmethionyl-leucyl-phenylalanine (fMLP) to the N-formyl peptide receptor (FPR), which leads to the production of O2–.
It was also found that AAT modulates the downstream activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and the translocation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase cytosolic components to the plasma membrane of neutrophils, which also contribute to the production of superoxide.
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“Our study identifies increased neutrophil NADPH oxidase and superoxide anion production by neutrophils of patients with AATD. Furthermore, it describes a mechanism whereby AAT modulates neutrophil signaling by binding fMLP thereby preventing receptor engagement,” the authors said.
The study found that circulating neutrophils collected from AATD patients had higher levels of p67phox and p47phox in the membrane, compared to neutrophils from healthy controls, leading to increased activation of NADPH oxidase and ultimately higher rates of superoxide production.
After the administration of AAT augmentation therapy, neutrophils collected from AATD patients displayed reduced levels of phox proteins and superoxide production closer to that seen in control cells.
“In patients receiving AAT augmentation, phox protein membrane assembly and oxidase activity was reduced after treatment. This study supports the use of AAT augmentation therapy to normalize neutrophil ROS production in AATD,” the authors summarized.
ROS that lead to oxidative stress on pulmonary tissue are believed to be among the driving factors of chronic obstructive pulmonary disease (COPD), and patients with AATD have a higher risk of developing COPD. This study showed that the augmentation of AAT levels may help reduce the levels of ROS in the body and help reduce the risk of COPD in AATD patients.
For the trial, 24 patients with AATD and 16 nonsmoking healthy control patients with AAT concentrations around 1.5 g/L were recruited. Neutrophils were isolated from the blood of participants and analyzed through assays as well as electrophoresis and immunoblotting. Blood samples from AATD patients were collected before augmentation therapy then again 2 days after therapy.
Hawkins P, McEnery T, Gabillard-Lefort C, et al. In vitro and in vivo modulation of NADPH oxidase activity and reactive oxygen species production in human neutrophils by α1-antitrypsin. ERJ Open Res. 2021;7(4):00234-02021. doi:10.1183/23120541.00234-2021