Abstract
Background: Ventilator-induced lung injury (VILI) contributes to the mortality in patients with acute lung injury by increasing inflammation. VILI is associated with neutrophil. Neutrophils release DNA and granular proteins as neutrophil extracellular traps (NETs). There is emerging evidence that NETs play important roles in inflammatory processes.
Objective: We hypothesized that NETs were produced in a VILI model and may contribute to injury. And NET formation (NETosis) is dependent on TLR4 signaling.
Methods: In VILI mouse model with and without intratracheal DNase treatment, we assessed markers of lung injury and inflammation. NETs were assessed by immunofluorescence microscopy, BALF level of MPO-DNA complexes, citrullinated-histone H3 and extracellular DNA. To determine the role of TLR4 during NETosis in vivo, we compared the response of TLR4 gene–deficient (TLR4-/-) mice to wild-type mice in an model of VILI.
Results: W/D ratio, BALF cell, neutrophil, protein and cytokines, histologic scores were significantly increased in the VILI group compared to the control group (P < 0.001). The high tidal mechanical ventilation was required for significant induction of NETs markers (P < 0.05). DNase treatment significantly reduced NETs markers (P < 0.05) and lung injury(P < 0.001). After high tidal mechanical ventilation, NETs markers from TLR4-/- mice were significantly lower than in those from WT mice.
Conclusions: NETs were produced in the lung during VILI, and disruption of NETs with DNase reduces lung injury. NETs play a pathogenic role in the current model of VILI. NET formation during VILI through TLR4 signaling pathway.
- Copyright ©the authors 2016