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  2. TLR4/TRAF6/NOX2 signaling pathway is involved in ventilation-induced lung injury via endoplasmic reticulum stress in murine model

TLR4/TRAF6/NOX2 signaling pathway is involved in ventilation-induced lung injury via endoplasmic reticulum stress in murine model

  • Int Immunopharmacol. 2021 Jul;96:107774. doi: 10.1016/j.intimp.2021.107774.
Qi Zeng 1 Liu Ye 1 Maoyao Ling 1 Riliang Ma 1 Junda Li 1 Haishao Chen 1 Linghui Pan 2
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China; Perioperative Medicine Research Center, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
  • 2 Department of Anesthesiology, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China; Perioperative Medicine Research Center, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China. Electronic address: plinghui@hotmail.com.
Abstract

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.

Keywords

Endoplasmic reticulum stress; NADPH oxidase 2; Reactive oxygen species; TNF receptor associated factor 6; Toll-like receptor 4; Ventilation-induced lung injury.

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