Neutrophil α-defensins cause lung injury by disrupting the capillary-epithelial barrier

Khalil Bdeir, Abd Al Roof Higazi, Irina Kulikovskaya, Melpo Christofidou-Solomidou, Sergei A. Vinogradov, Timothy C. Allen, Steven Idell, Rose Linzmeier, Tomas Ganz, Douglas B. Cines

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Rationale: The involvement of neutrophil activation in the sentinel, potentially reversible, events inthepathogenesis of acute lung injury (ALI) is only partially understood. α-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. Objectives: To study the role of α-defensins in the pathogenesis of ALI in a clinically relevant setting using mice transgenic for polymorphonuclear leukocyte expression of α-defensins. Methods: Transgenic mice expressing polymorphonuclear leukocyte α-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. Measurements and Main Results: Acid aspiration induced neutrophil migration and release of α-defensins into lung parenchyma and airways. ALI was more severe in α-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, α-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. Conclusions: α-Defensins mediate ALI through LRP-mediated loss of capillary-epithelial barrier function, suggesting a potential new approach to intervention.

Original languageEnglish (US)
Pages (from-to)935-946
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume181
Issue number9
DOIs
StatePublished - May 1 2010

Keywords

  • Acute lung injury
  • Capillary-epithelial barrier
  • Low-density lipoprotein-related receptor
  • Receptor-associated protein
  • α-defensins

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Bdeir, K., Higazi, A. A. R., Kulikovskaya, I., Christofidou-Solomidou, M., Vinogradov, S. A., Allen, T. C., Idell, S., Linzmeier, R., Ganz, T., & Cines, D. B. (2010). Neutrophil α-defensins cause lung injury by disrupting the capillary-epithelial barrier. American Journal of Respiratory and Critical Care Medicine, 181(9), 935-946. https://doi.org/10.1164/rccm.200907-1128OC