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

Abstract

Neutrophil extracellular traps (NETs) facilitate the extracellular killing of pathogens. However, excessive NETs formation and poor degradation are associated with exacerbated immune responses and tissue injury. In this study, we investigated the role of NETs in lipopolysaccharide (LPS)-mediated acute lung injury (ALI) and assessed the use of DNase I, for the treatment of ALI. Additionally, we focused on the controversial issue of whether LPS directly induces NETs release in vitro. NETs formation was detected in murine ALI tissue in vivo and was associated with increased NETs markers, citrullinated-histone H3 tissue levels and NET-DNA levels in BALF. Treatment with DNase I significantly degraded NETs and reduced citrullinated-histone H3 levels, which protected against ALI and ameliorated pulmonary oedema and total protein in BALF. In addition, DNase I significantly reduced IL-6 and TNF-α levels in plasma and BALF. In vitro, LPS-activated platelets rather than LPS alone efficiently induced NETs release. In conclusion, NETs formed during LPS-induced ALI, caused organ damage and initiated the inflammatory response. NETs degradation by DNase I promoted NET-protein clearance and protected against ALI in mice; thus, DNase I may be a new potential adjuvant for ALI therapy. Specifically, LPS induced NETs formation in an indirect manner via platelets activation.

Neutrophil extracellular traps in COVID-19

“…NETs present and stabilize a variety of oxidant enzymes in the extracellular space, including MPO, NADPH oxidase, and nitric oxide synthase (45), while also serving as a source of extracellular histones that carry significant cytotoxic potential (46,47). In light of these toxic cargo, it is not surprising that NETs play a role in a variety of lung diseases including cystic fibrosis (where they occlude larger airways) (48), smoking-related lung disease (49), and, with particular relevance here, pathogen-induced acute lung injury and ARDS (13,50,51). NETs have also been very well studied in the setting of cardiovascular disease where they infiltrate and propagate inflammation in the vessel wall (52), and, when formed intravascularly, occlude arteries (53), veins (54), and microscopic vessels (55).…”

Neutrophil calprotectin identifies severe pulmonary disease in COVID-19

“…One consideration is NET release (39,40). NETs are extracellular webs of DNA, histones, and microbicidal proteins that appear to perpetuate many types of lung disease including smoking-related disease (41), cystic fibrosis (42), and ARDS (14,43,44). NETs leverage calprotectin as an antimicrobial strategy against Candida (45) and Aspergillus (46), but, when left unchecked, NETs are also an important source of macrophage activation (47,48) and microvascular occlusion (49,50).…”

Amicus or Adversary Revisited: Platelets in Acute Lung Injury and Acute Respiratory Distress Syndrome

“…Histologic analysis and surrogate plasma assays indicate that NETs (Figure 3) form in lung microvessels and in vessels in other organs in experimental sepsis and that they contribute to physiologic dysfunction and outcomes (119)(120)(121)(122)(123)(124). Concentrations of plasma cell-free DNA, taken as a marker of NET formation, correlated with incidence and severity of ARDS in one study (120).…”