Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice

TY - JOUR

T1 - Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice

AU - Thomas, Grace M

AU - Carbo, Carla

AU - Curtis, Brian R

AU - Martinod, Kimberly

AU - Mazo, Irina B

AU - Schatzberg, Daphne

AU - Cifuni, Stephen M

AU - Fuchs, Tobias A

AU - von Andrian, Ulrich H

AU - Hartwig, John H

AU - Aster, Richard H

AU - Wagner, Denisa D

PY - 2012/6/28

Y1 - 2012/6/28

N2 - Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related death. The biologic processes contributing to TRALI are poorly understood. All blood products can cause TRALI, and no specific treatment is available. A "2-event model" has been proposed as the trigger. The first event may include surgery, trauma, or infection; the second involves the transfusion of antileukocyte antibodies or bioactive lipids within the blood product. Together, these events induce neutrophil activation in the lungs, causing endothelial damage and capillary leakage. Neutrophils, in response to pathogens or under stress, can release their chromatin coated with granule contents, thus forming neutrophil extracellular traps (NETs). Although protective against infection, these NETs are injurious to tissue. Here we show that NET biomarkers are present in TRALI patients' blood and that NETs are produced in vitro by primed human neutrophils when challenged with anti-HNA-3a antibodies previously implicated in TRALI. NETs are found in alveoli of mice experiencing antibody-mediated TRALI. DNase 1 inhalation prevents their alveolar accumulation and improves arterial oxygen saturation even when administered 90 minutes after TRALI onset. We suggest that NETs form in the lungs during TRALI, contribute to the disease process, and thus could be targeted to prevent or treat TRALI.

AB - Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related death. The biologic processes contributing to TRALI are poorly understood. All blood products can cause TRALI, and no specific treatment is available. A "2-event model" has been proposed as the trigger. The first event may include surgery, trauma, or infection; the second involves the transfusion of antileukocyte antibodies or bioactive lipids within the blood product. Together, these events induce neutrophil activation in the lungs, causing endothelial damage and capillary leakage. Neutrophils, in response to pathogens or under stress, can release their chromatin coated with granule contents, thus forming neutrophil extracellular traps (NETs). Although protective against infection, these NETs are injurious to tissue. Here we show that NET biomarkers are present in TRALI patients' blood and that NETs are produced in vitro by primed human neutrophils when challenged with anti-HNA-3a antibodies previously implicated in TRALI. NETs are found in alveoli of mice experiencing antibody-mediated TRALI. DNase 1 inhalation prevents their alveolar accumulation and improves arterial oxygen saturation even when administered 90 minutes after TRALI onset. We suggest that NETs form in the lungs during TRALI, contribute to the disease process, and thus could be targeted to prevent or treat TRALI.

KW - Acute Lung Injury

KW - Animals

KW - Blood Donors

KW - Blood Transfusion

KW - Cells, Cultured

KW - DNA

KW - Extracellular Space

KW - Humans

KW - Male

KW - Mice

KW - Mice, Inbred BALB C

KW - Neutrophil Activation

KW - Neutrophils

KW - Transplantation Immunology

KW - Transplantation, Homologous

U2 - 10.1182/blood-2012-01-405183

DO - 10.1182/blood-2012-01-405183

M3 - SCORING: Journal article

C2 - 22596262

VL - 119

SP - 6335

EP - 6343

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 26

ER -