Hypoxia induces proinflammatory cytokines production in alpha-1 antitrypsin deficiency patients

Introduction: Alpha-1 antitrypsin deficiency (AATD) is a rare respiratory condition characterized by abnormal inflammation, where neutrophils play a key role. Excessive neutrophil activation leads to an increase in the oxygen (O2) intake, causing local hypoxia and increased tissue-injury capacity. Tissue hypoxia is part of the inflammatory process so neutrophils can function effectively under these conditions. However, the mechanisms by which neutrophils mediate tissue damage under hypoxia remain unclear. The study aimed to determine whether hypoxia modifies the cytokine profile in AATD patients. Methods: Neutrophils from 22 AATD patients (6 MZ; 9 SZ; 7 ZZ) and 7 controls (MM) were exposed to hypoxia (1% O2) or normoxia (21% O2) for 4hrs. Pro- and anti-inflammatory cytokine levels were measured with a Luminex Bead-Based Multiplex Assay. Results: Neutrophils from AATD patients (SZ; ZZ) exposed to hypoxia showed an augmented proinflammatory cytokines release (IL-8, IL-12, IL-6, IL-23, IL-4, MIPα, MIPβ) compared to those of controls. Interestingly, the tumour necrosis factor (TNFα) is decreased in AATD patients compared to controls. Conclusion: Hypoxia increases the neutrophil release of proinflammatory cytokines in AATD patients compared to controls, contributing to lung damage in these patients. Funding: Sociedad Valenciana de Neumologia 2015 and 2017 and ISCIII PI17/01250 grants and European Regional Development Funds