• COPD ÀÜ Mechanisms
• Emphysema
• Oxidative Stress
• Rare lung diseases

α-1 Antitrypsin deficiency (AATD) is a rare genetic and hereditary condition characterised by low circulating levels of the α-1 antitrypsin (AAT) protein, a serine protease inhibitor that protects lung tissues from damage caused by proteolytic enzymes, such as neutrophil elastase and proteinase-3. Deficiency of circulating AAT is associated with an increased risk of developing emphysema, hepatic cirrhosis, panniculitis, bronchiectasis and vasculitis.1

Clinical data indicate that there is a great variability in the severity of the symptoms found in patients with AATD, and neither plasma AAT levels nor phenotype are sufficient to identify those patients who will develop severe lung or liver disease, indicating that there may be other mechanisms, in addition to the protease-antiprotease imbalance, that contribute to the development of emphysema or liver disease.2 Recent studies in animal models have shown an association between oxidative stress (OS) and the pathophysiology of AATD.3 ,4

We hypothesised that OS is increased in patients with AATD at early stages before the development of severe clinical manifestations. Thus, the present study was undertaken to investigate the role of OS in children with AATD. The OS status was evaluated in plasma by monitoring the total glutathione, the oxidised versus reduced glutathione ratio (GSSG/GSH), the oxidation products 8-hydroxydeoxyguanosine (8-OHdG), malonyldialdehyde (MDA) and protein carbonyl (PC), and the activity of the main antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GRd).

Fifty-one children diagnosed with AATD, and 38 control individuals, were prospectively included in the study. Demographic and clinical characteristics of patients included in the study are presented in online supplementary table S1. There were no differences in age, sex, Body Mass Index and lung or liver damage markers, and all the children were asymptomatic according to their physical status and the pulmonary and liver tests. Intermediate- (MZ; SZ) and high-risk (ZZ) patients showed significantly higher GSSG/GSH ratio (p=0.001; p<0.001, respectively), MDA (p=0.004; p<0.001), 8-OHdG (p<0.001; p<0.001) and PC (p=0.010; p=0.002) than the control group (MM). When compared with the control group, intermediate and high-risk patients showed significantly lower total glutathione (p<0.001; p<0.001), GSH levels (p<0.001; p<0.001), decreased CAT activity (p=0.003; p<0.001) and increased GPx activity (p=0.040; p<0.001) leading to an accumulation of hydrogen peroxide (p=0.040; p=0.001) (table 1 and see online supplementary figures E1–E4) that would explain the significantly increased levels of OS biomarkers observed in these patients (see online supplementary figure E5). No differences were observed between the control and the low-risk (MS; SS) groups. A gradation in OS parameters was observed when patients were compared among themselves, in that the expression of the Z allele produces a higher OS status in homozygous (ZZ) than in heterozygous (MZ;SZ) patients (see online supplement for results and discussion on multiple hypothesis testing).

In conclusion, our study supports the hypothesis that OS is a feature of AATD at early stages, and is associated with the presence of AAT Z protein. An increased chronic oxidative status could contribute to the higher risk of lung and liver damage observed in these patients, suggesting a rationale for the use of antioxidant therapies in the treatment of the disease.5