Liver X Receptor Agonist TO901317 Attenuates Paraquat-Induced Acute Lung Injury through Inhibition of NF-κB and JNK/p38 MAPK Signal Pathways.

Xiao Hu,Haitao Shen,Yu Wang,Min Zhao

doi:10.1155/2017/4652695

Xiao Hu, Haitao Shen + Show 2 more

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https://doi.org/10.1155/2017/4652695

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Abstract

Paraquat (PQ) is a widely used herbicide with extremely high poisoning mortality mostly from acute lung injury (ALI) or progressive pulmonary fibrosis. Toxicity mechanisms remain unclear, but a redox cycling process that generates reactive oxygen species (ROS) is involved, as are inflammation and cell apoptosis. We established an ALI mouse model by intraperitoneal injection of PQ (28 mg/kg) and then investigated the effects of a potent liver X receptor (LXR) agonist, TO901317 (5 or 20 mg/kg), injected intraperitoneally 30 min after PQ administration. Poisoned mice exhibited severe lung tissue lesions and edema, significant neutrophilic (PMNs) infiltration, and release of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). PQ administration also decreased activity of antioxidases, including superoxide dismutase (SOD), catalase (CAT), and glutathione S-transferases (GSTs), and increased lipid peroxidation as evaluated by malondialdehyde (MDA) levels. PQ exposure induced upregulation of the proapoptotic gene Bax and downregulation of the antiapoptotic gene Bcl-2, leading to marked cell apoptosis in the lung tissues. TO901317 treatment reversed all these effects through inhibition of PQ-induced nuclear factor kappa B (NF-κB) and JNK/p38 mitogen-activated protein kinase (MAPK) activation. The LXR agonist TO901317 had potent antioxidant, anti-inflammatory, and antiapoptotic effects against PQ-induced ALI.

Highlights

IntroductionParaquat (PQ) is a widely used herbicide with extremely high poisoning mortality due to high toxicity and lack of effective therapies
Paraquat (PQ) is a widely used herbicide with extremely high poisoning mortality due to high toxicity and lack of effective therapies. Because it is not expensive and is easy to access, the prevalence of PQ poisoning has increased dramatically: numerous fatalities have occurred in the past two decades in China [1]. Most of these patients died of acute lung injury (ALI) or progressive pulmonary fibrosis, because PQ tends to accumulate in lung tissue through the polyamine uptake system and so the pulmonary concentration becomes much higher than that in plasma and other organs [2]
At 72 h after PQ exposure, the body weight of mice in PQ group significantly declined compared with control group

Summary

Introduction

Paraquat (PQ) is a widely used herbicide with extremely high poisoning mortality due to high toxicity and lack of effective therapies. Because it is not expensive and is easy to access, the prevalence of PQ poisoning has increased dramatically: numerous fatalities have occurred in the past two decades in China [1]. ROS can extract hydrogen atoms from polyunsaturated fatty acids, causing lipid peroxidation. This process results in structural alterations and dysfunction of cell membranes, leading to cell damage or apoptosis [3]

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