Role of human neutrophil peptides in lung inflammation associated with α1-antitrypsin deficiency

Abstract
Individuals with α1-antitrypsin (α1-AT) deficiency are at risk for early-onset destructive lung disease as a result of insufficient lower respiratory tract α1-AT and an increased burden of neutrophil products such as elastase. Human neutrophil peptides (HNP), the most abundant protein component of neutrophil azurophilic granules, represent another potential inflammatory component in lung disease characterized by increased numbers of activated or deteriorating neutrophils. The purpose of this study was to determine the role of HNP in lower respiratory tract inflammation and destruction occuring in α1-AT deficiency. α1-AT-deficient individuals ( n = 33) and healthy control subjects ( n = 21) were evaluated by bronchoalveolar lavage. HNP concentrations were significantly higher in α1-AT-deficient individuals (1,976 ± 692 vs. 29 ± 12 nM, P < 0.0001), and levels correlated with markers of neutrophil-mediated lung inflammation. In vitro, HNP produced a dose-dependent cytotoxic effect on alveolar macrophages and stimulated production of the potent neutrophil chemoattractants leukotriene B4and interleukin-8 by alveolar macrophages, with a 6- to 10-fold increase in chemoattractant production over negative control cultures ( P < 0.05). A synergistic effect was noted between HNP and neutrophil elastase with regard to leukotriene B4production. Importantly, the proinflammatory effects of HNP were blocked by α1-AT. HNP likely play an important role in amplifying and maintaining neutrophil-mediated inflammation in the lungs.