Dexmedetomidine reduces ventilator-induced lung injury (VILI) by inhibiting Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signaling pathway

Hongli Chen,Xiaoqian Yu,Dejie Liu,Jingui Yu,Xiaotong Sun,Huanliang Wang,Xiaomei Yang,Jianbo Wu,Wenbo Yi,Yang Wang,Yonghao Hou

doi:10.17305/bjbms.2018.2400

Abstract

Mechanical ventilation (MV) may lead to ventilator-induced lung injury (VILI). Previous research has shown that dexmedetomidine attenuates pulmonary inﬂammation caused by MV, but the underlying mechanisms remain unclear. Our study aims to test whether dexmedetomidine has a protective effect against VILI and to explore the possible molecular mechanisms using the rat model. Thirty adult male Wistar rats weighing 200-250 g were randomly assigned to 5 groups (n = 6): control, low tidal volume MV (LMV), high tidal volume (HVT) MV (HMV), HVT MV + dexmedetomidine (DEX), HVT MV + dexmedetomidine + yohimbine (DEX+Y). Rats were euthanized after being ventilated for 4 hours. Pathological changes, lung wet/dry (W/D) weight ratio, lung myeloperoxidase (MPO) activity, levels of inflammatory cytokines (i.e., interleukin [IL]-1β, tumor necrosis factor alpha [TNF-α], and IL-6) in the bronchoalveolar lavage fluid (BALF) and lung tissues, expression of Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB, and activation of NF-κB in lung tissues were measured. Compared with HMV, DEX group showed fewer pathological changes, lower W/D ratios and decreased MPO activity of the lung tissues and lower concentrations of the inflammatory cytokines in the BALF and lung tissues. Dexmedetomidine significantly inhibited the expression of TLR4 and NF-κB and activation of NF-κB. Yohimbine partly alleviated the effects of dexmedetomidine. Dexmedetomidine reduced the inflammatory response to HVT-MV and had a protective effect against VILI, with the inhibition of the TLR4/NF-κB signaling pathway, at least partly via α2-adrenoceptors.

Highlights

Mechanical ventilation (MV) is an irreplaceable therapeutic measure for some critically ill patients [1]
Our study aims to test whether treatment with dexmedetomidine has a protective effect against ventilator-induced lung injury (VILI), induced by hightidal volume MV (HVT-MV) in a rat model, and to explore the function of the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signaling pathway in the anti-inflammatory process of dexmedetomidine in the VILI model
The results indicated that TLR4 plays a role in the development of VILI in the absence of infection, and that dexmedetomidine could reduce the expression of TLR4 in the VILI model

Summary

Introduction

Mechanical ventilation (MV) is an irreplaceable therapeutic measure for some critically ill patients [1]. There are several disadvantages of MV associated with the abnormal stretch and strain that may induce an iatrogenic lung injury known as ventilator-induced lung injury (VILI) [2,3]. Ample evidence has demonstrated that, in addition to mechanical damage, upregulation of inflammatory molecules and excessive inflammatory response play a crucial role in the occurrence and development of VILI [4,5]. Dexmedetomidine is widely used in patients subjected to MV. A few studies demonstrated that dexmedetomidine can attenuate pulmonary inflammation in animal models of VILI, but the underlying molecular mechanisms have not yet been explained [9]

Methods

Results

Discussion

Conclusion