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 non-cardiac 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 around 20-40%. However, ALI/ARDS continues to be a major factor in global burden of diseases, with no pharmacologic 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 TGFβ 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. While neutralization of extracellular histones / NETs, C5a and TGFβ is effective in experimental models of ALI/ARDS, controlled clinical trials will be necessary for further evaluation in future.

Neutrophil extracellular traps are indirectly triggered by lipopolysaccharide and contribute to acute lung injury

“…This may occur because DNase I splits only NETs formed by neutrophil exudation into the alveoli rather than capillary-associated NETs. Alternatively, NETs processing by DNase I may facilitate their clearance by macrophages1516.…”

Experimental design of complement component 5a-induced acute lung injury (C5a-ALI): a role of CC-chemokine receptor type 5 during immune activation by anaphylatoxin

“…The exudative phase of ARDS is characterized by an intra‐alveolar accumulation of inflammatory cells, the development of protein‐rich edema, hemorrhage, and the formation of alveolar hyaline membranes (1). Substantial evidence implies a role for pattern recognition receptors, cytokine release, neutrophil extracellular traps, complement activation, production of reactive oxygen species in this process (4, 5). Under homeostatic conditions, the fluid lining of airways and alveoli contains substantial amounts of locally produced complement components that provide protection against inhaled pathogens (6).…”

“…Although patients with hereditary complement deficiencies may display severe and recurring respiratory tract infections (7), excessive activation of the complement cascade can be extremely detrimental in the lungs (8). A particularly deleterious role has been associated with alveolar generation of activated complement component 5 (C5)a (4,8).…”

The Role of Complement in Transfusion-Related Acute Lung Injury

“…Furthermore, it has been shown that ALI induced by H5N1 played a relevant role by excessive complement activation including C5a generation [73]. Several murine in vivo studies using H1N1 and H5N1 as ALI inducers have shown beneficial effects of blocking C5a or C5aR in ALI [69,[72][73][74][75]. In addition, C5a can also directly impact vascular permeability by activating endothelial cells [22], which are also activated in TRALI [76].…”