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Monoclonal antibody against Toll-like receptor 4 attenuates ventilator-induced lung injury in rats by inhibiting MyD88- and NF-κB-dependent signaling

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The mechanisms through which mechanical ventilation causes non-infectious inflammatory diseases and lung injury are poorly understood. Animals models of this type of injury suggest that it involves signaling mediated by Tolllike receptor (TLR)4 and 9. In this study, in order to gain further insight into the involvement of TLR4 in this type of injury, we performed in vivo and in vitro experiments to determine the mechanisms through which TLR4 triggers inflammation. We also examined whether the use of TLR4 monoclonal antibody (mAb) can alleviate this type of injury. For this purpose, rats were tracheotomized and administered intratracheal injections of antiTLR4 mAb or saline, and then ventilated for 4 h at a high tidal volume (HTV) of 40 ml/ kg or allowed to breathe spontaneously for the same period of time (controls). Alveolar macrophages (AMs) were isolated from the bronchoalveolar lavage fluid (BALF) of the rats and stimulated for 16 h with tumor necrosis factor (TNF)α in the presence or absence of antiTLR4 mAb. Lung injury was assessed by examining lung histopathology, lung wet/dry weight ratio, BALF total protein and cytokine levels in BALF and plasma. The mRNA and protein expression levels of TLR4, TLR9, myeloid differentiation factor 88 (Myd88) and nuclear factor (NF)κB were measured in cultured macrophages. Compared to the controls (spontaneous breathing), the ventilated rats exhibited greater pulmonary permeability, more severe inflammatory cell infiltration/lung edema, and higher levels of interleukin (IL)1β, IL6 and TNFα in BALF and plasma. The AMs from the ventilated rats expressed higher mRNA and protein levels of TLR4, TLR9, Myd88 and NFκB compared with the macrophages from the spontaneously breathing rats. The ventilated rats pretreated with antiTLR4 mAb exhibited markedly attenuated signs of ventilationinduced injury, such as less lung inflammation and pulmonary edema, fewer cells in BALF, and lower levels of ILs and TNFα in BALF and plasma. Similarly, the TNFαdependent increases in the mRNA and protein expression of TLR4, Myd88 and NFκB in AMs were attenuated when TNFα was coadministered with antiTLR4 mAb than when TNF-α was administered alone. Coadministering anti-TLR4 mAb also reduced the TNFαdependent secretion of ILs. On the whole, our data demonstrate that TLR4 contributes significantly to ventilationinduced lung injury by activating the Myd88/NFκB pathway, and pretreating rats with antiTLR4 mAb partially protects them against this type of injury by inhibiting Myd88/NF-κB signaling.
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Document Type: Research Article

Affiliations: Department of Anesthesiology, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China

Publication date: January 1, 2017

More about this publication?
  • The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.

    The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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