title: Cytotoxic concentrations of alpha-defensins in the lungs of individuals with alpha 1-antitrypsin deficiency and moderate to severe lung disease.
abstract: The lungs of individuals with alpha(1)-antitrypsin (alpha(1)-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 alpha-defensins that are released upon activation. We hypothesized that in individuals with advanced lung disease associated with alpha(1)-AT deficiency cytotoxic concentrations of alpha-defensins might be present and unopposed, thus further aggravating lung disease. To evaluate this hypothesis, bronchoalveolar lavage was performed in 20 alpha(1)-AT deficient individuals with moderate to severe lung function impairment and 13 healthy volunteers. Cell counts as well as concentrations of NE and alpha-defensins were determined. While concentrations of NE were low (23+/-14nM) and alpha-defensins were undetectable in volunteers, they were significantly elevated in individuals with alpha(1)-AT deficiency (1313+/-723nM and 6605+/-2856nM, both p<0.0001). These concentrations were significantly higher than those found in a historical control of alpha(1)-AT deficient individuals with mild lung disease. Neutrophil numbers and NE concentration correlated with alpha-defensins concentration (r=0.612 and r=0.758, p=0.005 and p=0.0001, respectively). Individuals with alpha(1)-AT deficiency and moderate to severe lung function impairment have lung alpha-defensins concentrations in a range known to induce cytotoxicity in vitro in the absence of normal amounts alpha(1)-AT and thus may contribute to the development of lung disease in this population.
authors.affiliation: University of Florida, Gainesville, FL, USA. mwencker@aol.com
authors.forename: Marion
authors.initials: M
authors.lastname: Wencker
authors.forename: Mark L
authors.initials: ML
authors.lastname: Brantly
mesh_terms: D000328:Adult; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D005260:Female; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D008171:Lung Diseases / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D012720:Severity of Illness Index; D019896:alpha 1-Antitrypsin Deficiency / Q000378:metabolism*; D023084:alpha-Defensins / Q000009:adverse effects* / Q000378:metabolism* / Q000502:physiology
chemical_list: D023084:alpha-Defensins; D019272:Leukocyte Elastase