Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury
Axelle Caudrillier, … , Zena Werb, Mark R. Looney
Axelle Caudrillier, … , Zena Werb, Mark R. Looney
Published June 11, 2012
Citation Information: J Clin Invest. 2012;122(7):2661-2671. https://doi.org/10.1172/JCI61303.
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Research Article Pulmonology

Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury

Abstract

There is emerging evidence that platelets are major contributors to inflammatory processes through intimate associations with innate immune cells. Here, we report that activated platelets induce the formation of neutrophil extracellular traps (NETs) in transfusion-related acute lung injury (TRALI), which is the leading cause of death after transfusion therapy. NETs are composed of decondensed chromatin decorated with granular proteins that function to trap extracellular pathogens; their formation requires the activation of neutrophils and release of their DNA in a process that may or may not result in neutrophil death. In a mouse model of TRALI that is neutrophil and platelet dependent, NETs appeared in the lung microvasculature and NET components increased in the plasma. We detected NETs in the lungs and plasma of human TRALI and in the plasma of patients with acute lung injury. In the experimental TRALI model, targeting platelet activation with either aspirin or a glycoprotein IIb/IIIa inhibitor decreased NET formation and lung injury. We then directly targeted NET components with a histone blocking antibody and DNase1, both of which protected mice from TRALI. These data suggest that NETs contribute to lung endothelial injury and that targeting NET formation may be a promising new direction for the treatment of acute lung injury.

Authors

Axelle Caudrillier, Kai Kessenbrock, Brian M. Gilliss, John X. Nguyen, Marisa B. Marques, Marc Monestier, Pearl Toy, Zena Werb, Mark R. Looney

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Figure 4

Platelets and extracellular histones are therapeutic targets in TRALI.

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Platelets and extracellular histones are therapeutic targets in TRALI. (...
(A) Mice with TRALI (LPS plus H2Kd mAb) administered BWA3 mAb (10 mg/kg, i.v.) or IgG control (10 mg/kg) given immediately prior to H2Kd mAb. BWA3 mAb decreased extravascular lung water and lung vascular permeability to 125I-labeled albumin and decreased mortality compared with that in the IgG control group. Mean ± SD (n = 9). *P < 0.05 versus IgG control group. **P < 0.01. (B) Mice with TRALI (LPS plus H2Kd mAb) administered tirofiban (0.5 μg/g, i.v.) or PBS given immediately prior to H2Kd mAb. Tirofiban decreased extravascular lung water and lung vascular permeability to 125I-labeled albumin and decreased mortality compared with that in the PBS group. Mean ± SD (n = 7–9). **P < 0.01 versus PBS group. (C and D) MPO-DNA ELISA was used to quantify NET formation in the plasma of mice treated with (C) BWA3 mAb or (D) tirofiban compared with that in treatment controls and normal mouse plasma. Mean ± SD (n = 6). ***P < 0.001 versus control group; ††P < 0.01 versus IgG control and PBS groups. (E and F) Lung sections stained for NET formation (DNA, histone, and MPO) and for platelets (CD41). Representative images of mice with (E) TRALI given diluent (PBS) compared with those with (F) TRALI administered tirofiban. Mice treated with tirofiban have decreased NET formation and associated platelet sequestration compared with the PBS group. (n = 6). Scale bar: 20 μm.