Neutrophil Extracellular Traps Are Pathogenic in Primary Graft Dysfunction after Lung Transplantation

Sayah, David M.; Mallavia, Beñat; Liu, Fengchun; Ortiz-Muñoz, Guadalupe; Caudrillier, Axelle; Derhovanessian, Ariss; Ross, David J.; Lynch, Joseph P.; Saggar, Rajan; Ardehali, A.; Ware, Lorraine B.; Christie, Jason D.; Belperio, John A.; Looney, Mark R.

doi:10.1164/rccm.201406-1086oc

Cited by 210 publications

(186 citation statements)

References 46 publications

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“…To quantify NETs in human plasma, a capture ELISA based on Neutrophil Elastase (NE) associated with DNA was used 9. A detailed description is provided in the online supplementary data.…”

Section: Methodsmentioning

confidence: 99%

“…NETs formation allows activated neutrophils to release chromatin material interlaced with granular proteins and proteases, which traps pathogens but also damages endothelial cells and drives neutrophil recruitment to the lungs 7. An increase in NETs has been detected in plasma of patients with transfusion-related ARDS7 and is also implicated in the pathophysiology of ARDS of other aetiologies 8 9…”

Section: Introductionmentioning

confidence: 99%

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Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS

Hamid

Krasnodembskaya

Fitzgerald

et al. 2017

Thorax

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Rationale Platelets play an active role in the pathogenesis of acute respiratory distress syndrome (ARDS). Animal and observational studies have shown aspirin’s antiplatelet and immunomodulatory effects may be beneficial in ARDS. Objective To test the hypothesis that aspirin reduces inflammation in clinically relevant human models that recapitulate pathophysiological mechanisms implicated in the development of ARDS. Methods Healthy volunteers were randomised to receive placebo or aspirin 75 or 1200 mg (1:1:1) for seven days prior to lipopolysaccharide (LPS) inhalation, in a double-blind, placebo-controlled, allocation-concealed study. Bronchoalveolar lavage (BAL) was performed 6 hours after inhaling 50 μg of LPS. The primary outcome measure was BAL IL-8. Secondary outcome measures included markers of alveolar inflammation (BAL neutrophils, cytokines, neutrophil proteases), alveolar epithelial cell injury, systemic inflammation (neutrophils and plasma C-reactive protein (CRP)) and platelet activation (thromboxane B2, TXB2). Human lungs, perfused and ventilated ex vivo (EVLP) were randomised to placebo or 24 mg aspirin and injured with LPS. BAL was carried out 4 hours later. Inflammation was assessed by BAL differential cell counts and histological changes. Results In the healthy volunteer (n=33) model, data for the aspirin groups were combined. Aspirin did not reduce BAL IL-8. However, aspirin reduced pulmonary neutrophilia and tissue damaging neutrophil proteases (Matrix Metalloproteinase (MMP)-8/-9), reduced BAL concentrations of tumour necrosis factor α and reduced systemic and pulmonary TXB2. There was no difference between high-dose and low-dose aspirin. In the EVLP model, aspirin reduced BAL neutrophilia and alveolar injury as measured by histological damage. Conclusions These are the first prospective human data indicating that aspirin inhibits pulmonary neutrophilic inflammation, at both low and high doses. Further clinical studies are indicated to assess the role of aspirin in the prevention and treatment of ARDS. Trial registration number NCT01659307 Results.

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“…To quantify NETs in human plasma, a capture ELISA based on Neutrophil Elastase (NE) associated with DNA was used 9. A detailed description is provided in the online supplementary data.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS

Hamid

Krasnodembskaya

Fitzgerald

et al. 2017

Thorax

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show abstract

“…Of note, however, in murine pneumonia, thrombocytopenia enhanced lung inflammation and endothelial cell activation suggesting that platelet depletion strategies may be detrimental 148. The interplay between neutrophil extracellular traps and platelets is an emerging narrative in lung injury secondary to blood transfusion149 and following lung transplantation 150. Platelet-endothelial interaction may also play a role in regulating alveologenesis (see below,151) and hence lung repair after injury.…”

Section: Interactions Of the Lung Microvasculature With Leucocytes Anmentioning

confidence: 99%

The pulmonary endothelium in acute respiratory distress syndrome: insights and therapeutic opportunities

Millar

Summers

Griffiths

et al. 2016

Thorax

189

181

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The pulmonary endothelium is a dynamic, metabolically active layer of squamous endothelial cells ideally placed to mediate key processes involved in lung homoeostasis. Many of these are disrupted in acute respiratory distress syndrome (ARDS), a syndrome with appreciable mortality and no effective pharmacotherapy. In this review, we consider the role of the pulmonary endothelium as a key modulator and orchestrator of ARDS, highlighting advances in our understanding of endothelial pathobiology and their implications for the development of endothelial-targeted therapeutics including cell-based therapies. We also discuss mechanisms to facilitate the translation of preclinical data into effective therapies including the application of biomarkers to phenotype patients with ARDS with a predominance of endothelial injury and emerging biotechnologies that could enhance delivery, discovery and testing of lung endothelial-specific therapeutics.

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“…Conversely, there is substantial evidence that NETs and NETassociated factors, including histones and granule proteases, mediate vascular and tissue injury and that NET-mediated injury is a previously unrecognized mechanism of innate immune collateral damage to the host (1-3, 9, 12). Experimental models and limited clinical observations suggest that intra-or extravascular NET formation contributes to tissue injury in bacteremia (9,13,14), transfusion-related acute lung injury (15), primary graft dysfunction after lung transplantation (16), sterile vasculopathies and immune inflammation (17,18), thrombosis (19), and influenza (20). Thus, NET formation may be an important maladaptive activity of neutrophils (1) if it is triggered inappropriately or is unregulated in infection and inflammation.…”

Section: Introductionmentioning

confidence: 99%

Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation

Yost

Schwertz

Cody

et al. 2016

Journal of Clinical Investigation

123

133

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Neutrophil Extracellular Traps Are Pathogenic in Primary Graft Dysfunction after Lung Transplantation

Cited by 210 publications

References 46 publications

Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS

Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS

The pulmonary endothelium in acute respiratory distress syndrome: insights and therapeutic opportunities

Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation

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