Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 181, Issue 9, Pages 935-946Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.200907-1128OC
Keywords
acute lung injury; capillary-epithelial barrier; alpha-defensins; low-density lipoprotein-related receptor; receptor-associated protein
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Funding
- National Institutes of Health (Texas) [PO1 HL076406, 5RO1-CA1333470-02]
- Institute for Translational Medicine and Therapeutics (ITMAT)
- University of Pennsylvania Research Foundation
- Attenuon, LLC
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Rationale: 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. Objectives: To study the role of alpha-defensins in the pathogenesis of All in a clinically relevant setting using mice transgenic for polymorphonuclear leukocyte expression of alpha-defensins. Methods: 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. Measurements and Main Results: 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. Conclusions: alpha-Defensins mediate ALI through LRP-mediated loss of capillary-epithelial barrier function, suggesting a potential new approach to intervention.
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