Neutrophil Extracellular Traps Are Elevated in Patients with Pneumonia-related Acute Respiratory Distress Syndrome

Abstract

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Neutrophil extracellular traps have been associated with tissue damage. Whether these are involved in the pathogenesis of human acute respiratory distress syndrome (ARDS) and could be a potential therapeutic target is unknown. The authors quantified bronchoalveolar and blood neutrophil extracellular traps in patients with pneumonia-related ARDS and assessed their relationship with ventilator-free days. Methods Immunocompetent patients with pneumonia and moderate or severe ARDS (n = 35) and controls (n = 4) were included in a prospective monocentric study. Neutrophil extracellular trap concentrations were quantified (as DNA–myeloperoxidase complexes) in bronchoalveolar lavage fluid and serum by enzyme-linked immunosorbent assay. The relationship between bronchoalveolar lavage neutrophil extracellular trap concentrations and the primary clinical endpoint (i.e., the number of live ventilator-free days at day 28) was assessed using linear regression analyses. Results There was no significant relationship between bronchoalveolar lavage neutrophil extracellular trap concentrations and ventilator-free days by multiple regression analysis (β coefficient = 2.40; 95% CI, −2.13 to 6.92; P = 0.288). Neutrophil extracellular trap concentrations were significantly higher in bronchoalveolar lavage than in blood of ARDS patients (median [first to third quartiles]:154 [74 to 1,000] vs. 26 [4 to 68] arbitrary units, difference: −94; 95% CI, −341 to −57; P < 0.0001). Bronchoalveolar concentrations of patients were higher than those of controls (154 [74 to 1,000] vs. 4 [4 to 4] arbitrary units, difference: −150; 95% CI, −996 to −64; P < 0.001) and associated with bronchoalveolar interleukin-8 (Spearman’s ρ = 0.42; P = 0.012) and neutrophil concentrations (ρ = 0.57; P < 0.0001). Intensive care unit mortality (12%, n = 2 of 17 vs. 17%, n = 3 of 18; P > 0.99) and the number of ventilator-free days at day 28 (22 [14 to 25] vs. 14 [0 to 21] days; difference: −5; 95% CI, −15 to 0; P = 0.066) did not significantly differ between patients with higher (n = 17) versus lower (n = 18) bronchoalveolar neutrophil extracellular trap concentrations. Conclusions Bronchoalveolar neutrophil extracellular trap concentration was not significantly associated with mechanical ventilation duration in pneumonia-related ARDS.

Targeting potential drivers of COVID-19: Neutrophil extracellular traps

“…Indeed, NET levels in plasma are higher in patients with transfusion-associated ARDS than in subjects without ARDS (Caudrillier et al, 2012). Furthermore, neutrophils from patients with pneumonia-associated ARDS appear “primed” to form NETs, and both the extent of priming and the level of NETs in blood correlate with disease severity and mortality (Adrover et al, 2020; Bendib et al, 2019; Ebrahimi et al, 2018; Lefrançais et al, 2018; Mikacenic et al, 2018). Extracellular histones, likely partly originating from NETs, are elevated in the bronchoalveolar lavage fluid and plasma of ARDS patients (Lv et al, 2017).…”

A Comprehensive Literature Review on the Clinical Presentation, and Management of the Pandemic Coronavirus Disease 2019 (COVID-19)

“…Vitamin C reinforces the maintenance of the alveolar epithelial barrier and transcriptionally upregulates the protein channels (CFTR, aquaporin-5, ENaC, and Na+/K+ ATPase) regulating the alveolar fluid clearance [37]. HDIVC has been implicated in reducing plasma cell-free DNA formed from the neutrophil extracellular trap (NET) which is the facilitator of systemic inflammation in sepsis-induced multi-organ failure [38,39]. Interestingly, elevated levels of syndecan-1 in the plasma correlate with increased mortality in severe sepsis and ARDS, and this endothelial glycocalyx can be reduced significantly by HDIVC [39].…”

Serial change of neutrophil extracellular traps in tracheal aspirate of patients with acute respiratory distress syndrome: report of three cases

“…NETs have been detected in various sites (bronchoalveolar lavage fluid, lung tissue, and plasma) in ARDS patients [8][9][10][11][12]. The timing of sampling was heterogenous in these previous reports, and thus, the timing of the onset and transition of NET formation in these ARDS patients were unclear.…”

“…The association between NETs and ARDS in humans has been reported in bacterial pneumonia [8], ventilatorassociated pneumonia [9], transfusion-related acute lung injury [10], sepsis [11], and trauma [12]. These reports all suggested an association between the quantity of NETs and the severity of ARDS: in other words, "the more NETs, the more severe ARDS."…”

“…Previous reports suggested that NET formation was associated with ARDS and was also related to the severity of ARDS [8][9][10][11][12]. These reports assessed the amount of NETs by quantifying DNA and histones in alveolar lavage fluid, lung tissue, or plasma by cross-sectional analysis compared to controls or healthy people.…”