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

Abstract

Introduction: 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.

Areas covered: 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-β, 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.

Expert opinion: 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-β is effective in experimental models of ALI/ARDS, controlled clinical trials will be necessary for further evaluation in future.

Keywords: C5a; TGF-β; antibody; extracellular histones; inflammation; neutrophil extracellular traps.

Figure 1

Infusion of extracellular histones (75 mg/kg body weight i.v.) purified from calf thymus mediates lethality in C57BL/6J mice. Death of mice was preceded by clinical signs of respiratory failure. This figure shows data by Bosmann and Ward, which are consistent with reported findings by Xu et al. .

Figure 2

Neutralization of extracellular histones using monoclonal anti-H4 antibody reduces the severity of ALI in C57BL/6J mice. ALI was induced by intra-tracheal administration of recombinant mouse C5a (500 ng/mouse). Groups of mice were treated with either anti-Histone antibody (300 μg/mouse) or non-specific matched isotype IgG1κ antibody (300 μg/mouse). Severity of ALI was determined by quantification of albumin (ELISA) in broncho-alveolar lavage fluids after 8 h. Data taken from ).

Figure 3

Current concepts on the pathophysiologic mechanisms of ALI/ARDS involving extracellular histones / NETs, C5a and TGFβ. The frame on the left shows the architecture of the alveolus, which is composed of type I and type II alveolar epithelial cells, resident intra-alveolar macrophages and adjacent lung capillaries with intact endothelial lining. The frame on the right displays the injured alveolus in ALI/ARDS: Complement activation products (C5a) and inflammatory mediators released by activated macrophages orchestrate the influx of PMNs, monocytes and adaptive immune cells to the alveolar compartment. C5a promotes release of NETs and extracellular histones, thereby resulting in tissue damage and disruption of the epithelial/endothelial barrier. Intra-alveolar hemorrhage includes the presence of platelets, which interact with NETs and release TGFβ. The later phases of ALI/ARDS may include TGFβ-mediated fibro-proliferative responses and accumulation of extracellular matrix.