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Am J Physiol Lung Cell Mol Physiol 280: L947-L954, 2001;
1040-0605/01 $5.00
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Vol. 280, Issue 5, L947-L954, May 2001

Neutrophil defensins mediate acute inflammatory response and lung dysfunction in dose-related fashion

Haibo Zhang1, Giuliana Porro1, Neil Orzech1, Brendan Mullen2, Mingyao Liu3, and Arthur S. Slutsky1

1 Departments of Anaesthesia and Critical Care Medicine, St. Michael's Hospital, Toronto M5B 1W8; 2 Department of Pathology and Laboratory Medicine, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto M5G 1X5; and 3 Division of Thoracic Surgery, Toronto General Hospital, University of Toronto, Toronto, Ontario M5G 2C4, Canada

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 O2 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.

cytokine; inflammatory lung disease; human neutrophil peptides


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