TLR4/TRAF6/NOX2 signaling pathway is involved in ventilation-induced lung injury via endoplasmic reticulum stress in murine model
•HTV mechanical ventilation activate TLR4/TRAF6/NOX2 signaling pathway.•NOX2 mediated ROS production activate ER stress response during VILI.•Inhibition of TLR4/TRAF6/NOX2 signaling pathway attenuate the ER stress response and alleviate VILI. In ventilation-induced lung injury (VILI), prolonged nonp...
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Veröffentlicht in: | International immunopharmacology 2021-07, Vol.96, p.107774-107774, Article 107774 |
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Sprache: | eng |
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Zusammenfassung: | •HTV mechanical ventilation activate TLR4/TRAF6/NOX2 signaling pathway.•NOX2 mediated ROS production activate ER stress response during VILI.•Inhibition of TLR4/TRAF6/NOX2 signaling pathway attenuate the ER stress response and alleviate VILI.
In ventilation-induced lung injury (VILI), prolonged nonpathogen-mediated inflammation is triggered as a result of alveolar hyperinflation. In our previous study, we suggested that endoplasmic reticulum (ER) stress-mediated inflammation was involved in VILI, but how ER stress is triggered remains unknown. Toll-like receptor 4 (TLR4) activation plays an important role in mechanical ventilation (MV)-induced lung inflammation, however, it is unknown whether ER stress is activated by TLR4 to participate in VILI. In this study, C57BL/6 mice were exposed to MV with high tidal volumes (HTV 20 ml/kg). Mice were pretreated with TAK-242 the TLR4 inhibitor, C25-140, the TRAF6 inhibitor, or GSK2795039, the NOX2 inhibitor. Lung tissue and bronchoalveolar lavage fluid (BALF) were collected to measure lung injury, inflammatory responses and mRNA/protein expression associated with ER stress and the TLR4/TRAF6/NOX2 signaling pathway. Our results indicate that MV with HTV caused the TLR4/TRAF6/NOX2 signaling pathway activation and production of large amounts of ROS, which led to ER stress and NF-κB mediated inflammation in VILI. Furthermore, TLR4/TRAF6/NOX2 signaling pathway inhibition attenuated ER stress response and alleviate lung injury in mice. |
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ISSN: | 1567-5769 1878-1705 |
DOI: | 10.1016/j.intimp.2021.107774 |