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Protein-based therapies for acute lung injury: targeting neutrophil extracellular traps.

ABSTRACT: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the acute onset of noncardiac respiratory insufficiency associated with bilateral lung infiltrations. During the past decade, mechanical ventilation strategies using low tidal volumes have reduced the mortality of ALI/ARDS to ? 20 - 40%. However, ALI/ARDS continues to be a major factor in global burden of diseases, with no pharmacological agents currently available.In this review, we discuss several inflammatory proteins involved in the molecular pathogenesis of ALI/ARDS. The complement cleavage product, C5a, is a peptide acting as a potent anaphylatoxin. C5a may trigger the formation of neutrophil extracellular traps (NETs) and release of histone proteins to the extracellular compartment during ALI/ARDS. NETs may activate platelets to release TGF-?, which is involved in tissue remodeling during the later phases of ALI/ARDS. Interception of C5a signaling or blockade of extracellular histones has recently shown promising beneficial effects in small animal models of ALI/ARDS.Novel protein-based strategies for the treatment of ALI/ARDS may inspire the hopes of scientists, clinicians, and patients. Although neutralization of extracellular histones/NETs, C5a, and TGF-? is effective in experimental models of ALI/ARDS, controlled clinical trials will be necessary for further evaluation in future.

SUBMITTER: Bosmann M

PROVIDER: S-EPMC4123211 | biostudies-other | 2014 Jun

REPOSITORIES: biostudies-other

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Protein-based therapies for acute lung injury: targeting neutrophil extracellular traps.

Bosmann Markus M Ward Peter A PA

Expert opinion on therapeutic targets 20140326 6

<h4>Introduction</h4>Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the acute onset of noncardiac respiratory insufficiency associated with bilateral lung infiltrations. During the past decade, mechanical ventilation strategies using low tidal volumes have reduced the mortality of ALI/ARDS to ∼ 20 - 40%. However, ALI/ARDS continues to be a major factor in global burden of diseases, with no pharmacological agents currently available.<h4>Areas covered</h4>In this review ...[more]

PMID: 24670033

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Project description:BackgroundThrombosis is linked to neutrophil release of neutrophil extracellular traps (NETs). NETs are proposed as a mechanism of resistance to thrombolysis. This study intends to analyze the composition of thrombi retrieved after mechanical thrombectomy, estimate the age and organization of thrombi, and evaluate associations with the use of thrombolysis, antiplatelets, and heparin.MethodsThis retrospective observational study involved 72 samples (44 from cerebral and 28 coronary arteries), which were stained with hematoxylin and eosin, anti-NE (neutrophil elastase) antibody, and anti-histone H2B (histone H2B) antibody, representing different components in NET formation, all detectable during the later stages of NETosis, for histochemical and digital quantification of NET content. The histological and morphological evaluations of the specimens were correlated, through univariate and mediation analyses, with clinical information and therapy administered before intervention.ResultsThe results demonstrated that the composition of cerebral and coronary thrombi differs, and there were significantly more lytic cerebral thrombi than coronary thrombi (66% versus 14%; P=0.005). There was a considerably higher expression of NETs in the cerebral thrombi as testified by the higher expression of H2B (P=0.031). Thrombolysis was remarkably associated with higher NE positivity (average marginal effect, 6.461 [95% CI, 0.7901-12.13]; P=0.02555), regardless of the origin of thrombi. There was no notable association between the administration of antiaggregant therapy/heparin and H2B/NE amount when adjusted for the thrombus location. Importantly, the age of the thrombus was the only independent predictor of NET content without any mediation of the thrombolytic treatment (P=0.014).ConclusionsThe age of the thrombus is the driving force for NET content, which correlates with impaired clinical outcomes. The therapy that is currently administered does not modify NET content. This study supports the need to investigate new pharmacological approaches added to thrombolysis to prevent NET formation or enhance their disruption, such as recombinant human DNase I (deoxyribonuclease I).

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Protein-based therapies for acute lung injury: targeting neutrophil extracellular traps.

Publications

Protein-based therapies for acute lung injury: targeting neutrophil extracellular traps.

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