Cytotoxic concentrations of α-defensins in the lungs of individuals with α1-antitrypsin deficiency and moderate to severe lung disease

The lungs of individuals with α1-antitrypsin (α1-AT) deficiency have a reduced antiprotease protective shield. Typically, numbers of neutrophils are elevated in the lungs of affected individuals, carrying large amounts of neutrophil elastase (NE) and α-defensins that are released upon activation. We hypothesized that in individuals with advanced lung disease associated with α1-AT deficiency cytotoxic concentrations of α-defensins might be present and unopposed, thus further aggravating lung disease. To evaluate this hypothesis, bronchoalveolar lavage was performed in 20 α1-AT deficient individuals with moderate to severe lung function impairment and 13 healthy volunteers. Cell counts as well as concentrations of NE and α-defensins were determined. While concentrations of NE were low (23±14 nM) and α-defensins were undetectable in volunteers, they were significantly elevated in individuals with α1-AT deficiency (1313 ± 723 nM and 6605 ± 2856 nM, both p < 0.0001). These concentrations were significantly higher than those found in a historical control of α1-AT deficient individuals with mild lung disease. Neutrophil numbers and NE concentration correlated with α-defensins concentration (r = 0.612 and r = 0.758, p = 0.005 and p = 0.0001, respectively). Individuals with α1-AT deficiency and moderate to severe lung function impairment have lung α-defensins concentrations in a range known to induce cytotoxicity in vitro in the absence of normal amounts α1-AT and thus may contribute to the development of lung disease in this population.