Neutrophil alpha-defensins cause lung injury by disrupting the capillary-epithelial barrier.
BACKGROUND
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.


OBJECTIVE
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.


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.


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.
Bdeir
Khalil
K
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA l9l04, USA.
Higazi
Abd Al-Roof
AA
Kulikovskaya
Irina
I
Christofidou-Solomidou
Melpo
M
Vinogradov
Sergei A
SA
Allen
Timothy C
TC
Idell
Steven
S
Linzmeier
Rose
R
Ganz
Tomas
T
Cines
Douglas B
DB
D055371:Acute Lung Injury / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002196:Capillaries / Q000502:physiology; D002199:Capillary Permeability; D004847:Epithelial Cells / Q000502:physiology; D018014:Gene Transfer Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000737:chemistry; D023084:alpha-Defensins / Q000378:metabolism / Q000502:physiology*
D023084:alpha-Defensins