The role of neutrophil extracellular traps in acute lung injury

Abstract

Acute lung injury (ALI) is a heterogeneous inflammatory condition associated with high morbidity and mortality. Neutrophils play a key role in the development of different forms of ALI, and the release of neutrophil extracellular traps (NETs) is emerging as a common pathogenic mechanism. NETs are essential in controlling pathogens, and their defective release or increased degradation leads to a higher risk of infection. However, NETs also contain several pro-inflammatory and cytotoxic molecules than can exacerbate thromboinflammation and lung tissue injury. To reduce NET-mediated lung damage and inflammation, DNase is frequently used in preclinical models of ALI due to its capability of digesting NET DNA scaffold. Moreover, recent advances in neutrophil biology led to the development of selective NET inhibitors, which also appear to reduce ALI in experimental models. Here we provide an overview of the role of NETs in different forms of ALI discussing existing gaps in our knowledge and novel therapeutic approaches to modulate their impact on lung injury.

Keywords: ALI (acute lung injury); ARDS (acute respiratory distress syndrome); COVID-19; DAMPs (damage-associated molecular patterns); NETs (neutrophil extracellular traps); Thromboinflammation; infections and sepsis; sterile inflammatory response.

Figure 1

Mechanisms of NET release and NET-mediated lung injury (A) Neutrophils release NETs in response to endogenous and exogenous stimuli. Endogenous factors include DAMPs, pro-inflammatory cytokines, mtDAMPs, and molecules released by activated platelets; exogenous factors include PAMPs associated with microbial infections. (B) Inhibition of NET generation and release. The contribution of platelets to NETosis can be attenuated by using platelet activation inhibitors; neutrophil chromatin decondensation can be targeted by using PAD4 inhibitors; neutrophil membrane permeabilization can be prevented by using gasderimin D inhibitors. (C) NETs comprise a DNA scaffold decorated with granule proteases and histone proteins. NET DNA scaffold can be digested by DNase; NET proteolytic activity can be abrogated by specific protease inhibitors. (D) NETs release contributes to the pathogenesis of ALI. NETs facilitate the formation of thrombi, promote endothelial cell activation, and induce microvascular injury. These microvascular alterations result in increased vascular permeability, intra-alveolar accumulation of protein-rich fluid, and infiltration of inflammatory cells. Image created by DS using BioRender (https://biorender.com/).

Figure 2

Association of NETs with different ALI/ARDS etiologies. Image created by DS using BioRender (https://biorender.com/).