Neutrophil degranulation and oxidative profile in patients with alpha-1 antitrypsin deficiency under hypoxic conditions

Introduction: The ability of neutrophils to damage adjacent tissues is related to their activation status. Excessive neutrophil activation leads to their degranulation and increases the oxygen (O2) intake, leading to local hypoxia and an increase in the reactive oxygen species (ROS) that contribute to tissue injury. Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition that can produce lung and liver damage in some patients. We have previously shown that oxidative stress is involved in the pathophysiology of AATD. This study was aimed to determine whether hypoxia induces neutrophil activation and modifies the oxidative profile in AATD patients. Methods: Neutrophils isolated from 33 AATD patients (SZ; ZZ) and 7 controls (MM) were exposed to hypoxia (1% O2 for 4hrs). Neutrophils’ degranulation markers and oxidative stress parameters were measured ELISA, flow cytometry and RT-qPCR. Results: Neutrophils from AATD patients exposed to hypoxia showed an augmented myeloperoxidase, lactoferrin and elastase release compared to those of the control group. Patient’s neutrophils showed increased ROS levels, mitochondrial superoxide anion and peroxidized lipids in hipoxia. An increase was also observed in mitochondrial superoxide dismutase, glutathione peroxidase, catalase and NRF2 expression, a regulator of the expression of antioxidant enzymes. Conclusion: Hypoxia increases neutrophil activation and ROS production in AATD patients when compared to healthy individuals. Patients’ antioxidant defense mechanisms are increased providing protection against exposure to the pro-oxidant environment caused by hypoxia. Funding: ISCIII PI17/01250 and Valencian society of pneumology 2017.