The Emerging Role of Neutrophil Extracellular Traps in Respiratory Disease

Neutrophil extracellular traps (NETs) are extrusions of intracellular DNA and attached granular material that enable bacterial killing. NETs are increasingly recognized for their role in the pathogenesis of respiratory disease. NETs are composed of a complex mix of intracellularly derived material that neutrophils organize within the cytoplasm and then expel in a nondirected manner in the vicinity of invading organisms. Combined, these trap and destroy multiple genera of microbes including bacteria, fungi, viruses, and protozoans, limiting infection especially where phagocytosis is not possible. At first, NET formation was thought to be a terminal event for neutrophils; however, it is now apparent that some neutrophils survive this process, becoming anuclear, and may drive ongoing tissue damage. NETs are now known to be directly cytotoxic to lung epithelium and endothelium, and their excessive production is seen in pneumonia and acute lung injury as well as several chronic diseases, including COPD, asthma, and cystic fibrosis. NETs also appear to play a role in both tumor defense and dissemination, depending on the local microenvironment and the specific tumor subtype. It is becoming increasingly apparent that NET formation can exert a positive or negative influence on multiple respiratory pathologies and that simply globally reducing or increasing NET formation is unlikely to be a therapeutic success. Rather, as our understanding grows, it is likely that targeted NET up- or downregulation along with destruction or protection of already formed NETs may become an additional point of intervention for respiratory physicians. Neutrophil extracellular traps (NETs) are extrusions of intracellular DNA and attached granular material that enable bacterial killing. NETs are increasingly recognized for their role in the pathogenesis of respiratory disease. NETs are composed of a complex mix of intracellularly derived material that neutrophils organize within the cytoplasm and then expel in a nondirected manner in the vicinity of invading organisms. Combined, these trap and destroy multiple genera of microbes including bacteria, fungi, viruses, and protozoans, limiting infection especially where phagocytosis is not possible. At first, NET formation was thought to be a terminal event for neutrophils; however, it is now apparent that some neutrophils survive this process, becoming anuclear, and may drive ongoing tissue damage. NETs are now known to be directly cytotoxic to lung epithelium and endothelium, and their excessive production is seen in pneumonia and acute lung injury as well as several chronic diseases, including COPD, asthma, and cystic fibrosis. NETs also appear to play a role in both tumor defense and dissemination, depending on the local microenvironment and the specific tumor subtype. It is becoming increasingly apparent that NET formation can exert a positive or negative influence on multiple respiratory pathologies and that simply globally reducing or increasing NET formation is unlikely to be a therapeutic success. Rather, as our understanding grows, it is likely that targeted NET up- or downregulation along with destruction or protection of already formed NETs may become an additional point of intervention for respiratory physicians. ResponseCHESTVol. 156Issue 6PreviewWe thank Bendib et al for their careful consideration of our article.1 We agree, given the potential benefits of targeting neutrophil extracellular traps (NETs) in the treatment of various lung diseases, more work is needed to better delineate their fundamental roles. The lack of consistent clinical definition of these conditions in published trials, the relatively small number of clinical studies, and the variation in timing in sampling from onset of symptoms only compounds the issue. Full-Text PDF Understanding the Role of Neutrophil Extracellular Traps in Patients With Severe Pneumonia and ARDSCHESTVol. 156Issue 6PreviewWe read with great interest the recently published CHEST article (October 2019) by Twaddell et al,1 which comprehensively reviewed the role of neutrophil extracellular traps (NETs) in respiratory diseases. As nicely depicted by the authors, NET release by neutrophils during a process termed NETosis has been shown to be associated with positive outcomes, including extracellular pathogens trapping and killing, and potentially negative ones, associated with tissue injury. Better delineating the roles of NETs in the pathophysiology of ARDS is of utmost importance because NETs could be potential therapeutic targets. Full-Text PDF