Neutrophil defensins mediate acute inflammatory response and lung dysfunction in dose-related fashion.
High concentrations of neutrophil defensins from airway and blood have been reported in patients with inflammatory lung diseases, but their exact role is unclear. We investigated the direct effect of defensins on the lungs of mice. Intratracheal instillation of purified defensins (5-30 mg/kg) induced a progressive reduction in peripheral arterial O(2) saturation, increased lung permeability, and enhanced the lung cytochrome c content. These indexes of acute lung dysfunction were associated with an increased total cell number and a significant neutrophil influx into the lung [5.1 +/- 0.04% in control vs. 48.6 +/- 12.7% in the defensin (30 mg/kg) group, P < 0.05]. Elastase concentrations in the bronchoalveolar lavage (BAL) fluids increased from 38 +/- 11 ng/ml (control) to 80 +/- 4 ng/ml (defensins, P < 0.05). Five hours after defensin instillation, concentrations of tumor necrosis factor-alpha and macrophage inflammatory protein-2 in BAL fluid were significantly increased. High levels of monocyte chemoattractant protein-1 in BAL fluid and plasma were also found after defensin stimulation. We conclude that intratracheal instillation of defensins causes acute lung inflammation and dysfunction, suggesting that high concentrations of defensins in the airways may play an important role in the pathogenesis of inflammatory lung diseases.
Zhang
H
H
Departments of Anaesthesia and Critical Care Medicine, St. Michael's Hospital, Toronto M5B 1W8, Ontario M5G 2C4, Canada. haibo.zhang@utoronto.ca
Porro
G
G
Orzech
N
N
Mullen
B
B
Liu
M
M
Slutsky
A S
AS
D000818:Animals; D001158:Arteries; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D018932:Chemokine CCL2 / Q000378:metabolism; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D023082:Defensins / Q000008:administration & dosage / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007322:Instillation, Drug; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D010092:Oximetry; D010196:Pancreatic Elastase / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D003574:Cytochrome c Group; D023082:Defensins; D014409:Tumor Necrosis Factor-alpha; D010196:Pancreatic Elastase