Alpha-1 antitrypsin and deoxyribonuclease 1 as potential therapies for the treatment of bronchiectasis.

Abstract

Background: The excessive production of proteases such as neutrophil elastase (NE) drives inflammation and the development of bronchiectasis; the main anti-protease is alpha-1 antitrypsin (AAT). A mechanism of lung protease expression is via neutrophil and macrophage extracellular trap formation (NETs/METs); which are broken down by deoxyribonuclease 1 (DNase 1). The ability of AAT and DNase 1 to reduce inflammation in vitro and in vivo was assessed. Method(s): AAT eluted from human serum and recombinant DNase 1 (dornase alfa/Pulmozyme) were used. In vitro experiments were performed using blood and bronchoalveolar lavage (BAL) samples from human subjects that were infected with influenza A virus (IAV) or nontypeable Haemophilus influenzae (NTHi) to upregulate NET/MET and NE expression; AAT and DNase 1 were added. In vivo experiments were performed in mice infected with IAV/NTHi and administered inhalational AAT and DNase 1 for 3 days. Result(s): Samples were obtained from 22 adults (mean age of 51 +/- 16 years). Infection induced prominent NET (Fig. 1A) and MET expression in vitro, which was reduced by the addition of DNase 1 (p<0.0001). AAT reduced NE expression in vitro (Fig. 1B), (p<0.0001). AAT reduced inflammation in infected mice as assessed by lung weight and BAL white cell count (n=8 mice, p<0.05) (Fig. 1C), this effect was enhanced by the addition of DNase 1. Conclusion(s): Alpha-1 antitrypsin reduces lung inflammation and this effect is enhanced by the addition of DNase 1.