Neutrophil [alpha]-Defensins Cause Lung Injury by Disrupting the Capillary-Epithelial Barrier

The involvement of neutrophil activation in the sentinel, potentially reversible, events in the pathogenesis of acute lung injury (ALI) is only partially understood. alpha-Defensins are the most abundant proteins secreted by activated human neutrophils, but their contribution to ALI in mouse models...

Full description

Saved in:
Bibliographic Details
Published inAmerican journal of respiratory and critical care medicine Vol. 181; no. 9; p. 935
Main Authors Bdeir, Khalil, Higazi, Abd Al-Roof, Kulikovskaya, Irina, Christofidou-Solomidou, Melpo, Vinogradov, Sergei A, Allen, Timothy C, Idell, Steven, Linzmeier, Rose, Ganz, Tomas, Cines, Douglas B
Format Journal Article
LanguageEnglish
Published New York American Thoracic Society 01.05.2010
Subjects
Artificial chromosomes
Edema
Granulocytes
Leukocytes
Lipoproteins
Lungs
Medical prognosis
Neutrophils
Pathogenesis
Peptides
Permeability
Proteins
Sepsis
Signal transduction
Transgenic animals
Online AccessGet full text

Cover

More Information
Summary:The involvement of neutrophil activation in the sentinel, potentially reversible, events in the pathogenesis of acute lung injury (ALI) is only partially understood. alpha-Defensins are the most abundant proteins secreted by activated human neutrophils, but their contribution to ALI in mouse models is hindered by their absence from murine neutrophils and the inability to study their effects in isolation in other species. To study the role of alpha-defensins in the pathogenesis of ALI in a clinically relevant setting using mice transgenic for polymorphonuclear leukocyte expression of alpha-defensins. Transgenic mice expressing polymorphonuclear leukocyte alpha-defensins were generated. ALI was induced by acid aspiration. Pulmonary vascular permeability was studied in vivo using labeled dextran and fibrin deposition. The role of the low-density lipoprotein-related receptor (LRP) in permeability was examined. Acid aspiration induced neutrophil migration and release of alpha-defensins into lung parenchyma and airways. ALI was more severe in alpha-defensin-expressing mice than in wild-type mice, as determined by inspection, influx of neutrophils into the interstitial space and airways, histological evidence of epithelial injury, interstitial edema, extravascular fibrin deposition, impaired oxygenation, and reduced survival. Within 4 hours of insult, alpha-defensin-expressing mice showed greater disruption of capillary-epithelial barrier function and ALI that was attenuated by systemic or intratracheal administration of specific inhibitors of the LRP. alpha-Defensins mediate ALI through LRP-mediated loss of capillary-epithelial barrier function, suggesting a potential new approach to intervention.
ISSN:1073-449X
1535-4970