title: Anti-human neutrophil antigen-3a induced transfusion-related acute lung injury in mice by direct disturbance of lung endothelial cells.
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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Behnaz
authors.initials: B
authors.lastname: Bayat
authors.forename: Yudy
authors.initials: Y
authors.lastname: Tjahjono
authors.forename: Akylbek
authors.initials: A
authors.lastname: Sydykov
authors.forename: Silke
authors.initials: S
authors.lastname: Werth
authors.forename: Stefan
authors.initials: S
authors.lastname: Hippenstiel
authors.forename: Nobert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Ulrich J
authors.initials: UJ
authors.lastname: Sachs
authors.forename: Sentot
authors.initials: S
authors.lastname: Santoso
mesh_terms: D000199:Actins / Q000378:metabolism; D055371:Acute Lung Injury / Q000209:etiology / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002199:Capillary Permeability / Q000276:immunology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007519:Isoantigens / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D026901:Membrane Transport Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics; D009504:Neutrophils / Q000276:immunology; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology*; D065227:Transfusion Reaction
chemical_list: D000199:Actins; D000906:Antibodies; C518134:HNA-3a antigen, human; D007519:Isoantigens; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C484524:SLC44A2 protein, human; C571060:SLC44A2 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: acute lung injury; endothelium; reactive oxygen species