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Maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury
Emma Lefrançais, … , Carolyn S. Calfee, Mark R. Looney
Emma Lefrançais, … , Carolyn S. Calfee, Mark R. Looney
Published February 8, 2018
Citation Information: JCI Insight. 2018;3(3):e98178. https://doi.org/10.1172/jci.insight.98178.
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Research Article Immunology Pulmonology

Maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury

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Abstract

Neutrophils dominate the early immune response in pathogen-induced acute lung injury, but efforts to harness their responses have not led to therapeutic advancements. Neutrophil extracellular traps (NETs) have been proposed as an innate defense mechanism responsible for pathogen clearance, but there are concerns that NETs may induce collateral damage to host tissues. Here, we detected NETs in abundance in mouse models of severe bacterial pneumonia/acute lung injury and in human subjects with acute respiratory distress syndrome (ARDS) from pneumonia or sepsis. Decreasing NETs reduced lung injury and improved survival after DNase I treatment or with partial protein arginine deiminase 4 deficiency (PAD4+/–). Complete PAD4 deficiency (PAD4–/–) reduced NETs and lung injury but was counterbalanced by increased bacterial load and inflammation. Importantly, we discovered that the lipoxin pathway could be a potent modulator of NET formation, and that mice deficient in the lipoxin receptor (Fpr2–/–) produced excess NETs leading to increased lung injury and mortality. Lastly, we observed in humans that increased plasma NETs were associated with ARDS severity and mortality, and lower plasma DNase I levels were associated with the development of sepsis-induced ARDS. We conclude that a critical balance of NETs is necessary to prevent lung injury and to maintain microbial control, which has important therapeutic implications.

Authors

Emma Lefrançais, Beñat Mallavia, Hanjing Zhuo, Carolyn S. Calfee, Mark R. Looney

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Figure 1

Neutrophil extracellular traps (NETs) are elaborated during MRSA- and PAO1-induced lung injury models.

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Neutrophil extracellular traps (NETs) are elaborated during MRSA- and PA...
(A) Mice were instilled intratracheally (i.t.) with methicillin-resistant Staphylococcus aureus (MRSA) at 5 × 107 CFU/mouse and sacrificed at indicated time points (n = 3–12). (A) Bronchoalveolar lavage (BAL) total protein concentration, (B) lung vascular permeability to radioactive albumin, (C) excess lung water, and (D) BAL WBC were all increased after infection. (E) BAL cytospin and (F) differential counts are composed mainly of neutrophils. Scale bar: 20 μm. (G) NETs (neutrophil elastase–DNA complexes) in BAL and (H) plasma. (I) BAL NETs and protein concentration are positively correlated (r = Pearson’s correlation coefficient). (J–M) Mice were instilled i.t. with Pseudomonas aeruginosa strain PAO1 at 1 × 107 or 5 × 107 CFU/mouse and sacrificed at 24 hours (n = 3–4). (J) BAL WBC, (K) BAL total protein concentration, (L) BAL NETs, and (M) plasma NETs were all increased after infection. Data were analyzed using 1-way ANOVA and Dunnett’s post test. *P ≤ 0.05,**P ≤ 0.01, ***P ≤ 0.001. ns, not significant.

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