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Arterioscler Thromb Vasc Biol. 2013 Nov;33(11):2538-48. doi: 10.1161/ATVBAHA.113.301206. Epub 2013 Sep 5.

Anti-human neutrophil antigen-3a induced transfusion-related acute lung injury in mice by direct disturbance of lung endothelial cells.

Author information

1
From the Institute for Clinical Immunology and Transfusion Medicine, Justus Liebig University, Giessen, Germany (B.B., Y.T., S.W., U.J.S., S.S.); Department of Internal Medicine II/V, ECCPS, University of Giessen and Marburg Lung Center (UGMLC), Member of the DZL, Giessen, Germany (A.S., N.W.); and Department of Infectious Diseases and Respiratory Medicine of the Charité Medical University, Berlin, Germany (S.H.).

Abstract

OBJECTIVE:

Antibodies against human neutrophil antigen-3a (HNA-3a) located on choline transporter-like protein 2 induce severe transfusion-related acute lung injury (TRALI). This study aims to identify the mechanism implicated in anti-HNA-3a-mediated TRALI.

APPROACH AND RESULTS:

Our analysis shows that anti-HNA-3a recognizes 2 choline transporter-like protein 2 isoforms (P1 and P2) on human microvascular endothelial cells from lung blood vessels but reacts only with the P1 isoform on neutrophils. Direct treatment of HNA-3a-positive endothelial cells with anti-HNA-3a, but not with anti-HNA-3b, leads to reactive oxygen species production, increased albumin influx, and decreased endothelial resistance associated with the formation of actin stress filaments and loosening of junctional vascular endothelium-cadherin. In a novel in vivo mouse model, TRALI was documented by significant increase in lung water content, albumin concentration, and neutrophil numbers in the bronchoalveolar lavage on injection of human anti-HNA-3a in lipopolysaccharides-treated, as well as nontreated mice. Interestingly, although neutrophil depletion alleviated severity of lung injury, it failed to prevent TRALI in this model. Infusion of anti-HNA-3a F(ab')2 fragments caused moderate TRALI. Finally, mice lacking nicotinamide adenine dinucleotide phosphate oxidase (NOX2(y/-)) were protected from anti-HNA-3a-mediated TRALI.

CONCLUSIONS:

These data demonstrate the initiation of endothelial barrier dysfunction in vitro and in vivo by direct binding of anti-HNA-3a on endothelial cells. It seems, however, that the presence of neutrophils aggravates barrier dysfunction. This novel mechanism of TRALI primarily mediated by endothelial cell dysfunction via choline transporter-like protein 2 may help to define new treatment strategies to decrease TRALI-related mortality.

KEYWORDS:

acute lung injury; endothelium; reactive oxygen species

PMID:
24008160
DOI:
10.1161/ATVBAHA.113.301206
[Indexed for MEDLINE]

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