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/).