Role of human neutrophil peptides in lung inflammation associated with alpha1-antitrypsin deficiency.
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 B(4) 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 B(4) 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.
Spencer
L Terry
LT
Division of Pulmonary Diseases, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32610-0296, USA. spenclt@peds.ufl.edu
Paone
Gregorino
G
Krein
Peter M
PM
Rouhani
Farshid N
FN
Rivera-Nieves
Jesus
J
Brantly
Mark L
ML
D000328:Adult; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D019272:Leukocyte Elastase / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D011014:Pneumonia / Q000276:immunology*; D000515:alpha 1-Antitrypsin / Q000494:pharmacology; D019896:alpha 1-Antitrypsin Deficiency / Q000276:immunology*; D023084:alpha-Defensins / Q000378:metabolism* / Q000494:pharmacology
D016209:Interleukin-8; D000515:alpha 1-Antitrypsin; D023084:alpha-Defensins; D007975:Leukotriene B4; D019272:Leukocyte Elastase