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Am J Physiol Lung Cell Mol Physiol 286: L514-L520, 2004. First published October 31, 2003; doi:10.1152/ajplung.00099.2003
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TRANSLATIONAL PHYSIOLOGY

Role of human neutrophil peptides in lung inflammation associated with {alpha}1-antitrypsin deficiency

L. Terry Spencer,1 Gregorino Paone,2 Peter M. Krein,2 Farshid N. Rouhani,2 Jesus Rivera-Nieves,2 and Mark L. Brantly3

1Division of Pulmonary Diseases, Department of Pediatrics, and 3Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Florida College of Medicine, Gainesville, Florida 32610; and 2Clinical Studies Section, Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892

Submitted 3 April 2003 ; accepted in final form 28 October 2003

Individuals with {alpha}1-antitrypsin ({alpha}1-AT) deficiency are at risk for early-onset destructive lung disease as a result of insufficient lower respiratory tract {alpha}1-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 {alpha}1-AT deficiency. {alpha}1-AT-deficient individuals (n = 33) and healthy control subjects (n = 21) were evaluated by bronchoalveolar lavage. HNP concentrations were significantly higher in {alpha}1-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 B4 and 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 B4 production. Importantly, the proinflammatory effects of HNP were blocked by {alpha}1-AT. HNP likely play an important role in amplifying and maintaining neutrophil-mediated inflammation in the lungs.

pulmonary emphysema; granulocytes; alveolar macrophages; serpins


Address for reprint requests and other correspondence: L. T. Spencer, Div. of Pulmonary Diseases, Dept. of Pediatrics, Univ. of Florida College of Medicine, PO Box 100296, Gainesville, FL 32610-0296 (E-mail: spenclt{at}peds.ufl.edu).




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