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JNK Inhibitor SP600125 Attenuates Paraquat-Induced Acute Lung Injury: an In Vivo and In Vitro Study

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Abstract

Acute lung injury (ALI) is a major complication soon after paraquat poisoning and rapidly progresses with high mortality. However, the specific mechanism underlying paraquat-induced ALI is still unclear. In this study, the mechanism underlying the protective effects of SP600125 on paraquat-induced ALI was investigated according to oxidative stress, inflammation, and apoptosis. The rats were randomly assigned into the control group (CON), the paraquat poisoning group (PQ), and the PQ + SP600125 group (SP). A549 cells were divided into the Con group, Pq group, and Sp group. H&E staining and detection of lung wet/dry ratio were employed to evaluate lung injury. Annexin V-PI staining was done to evaluate A549 cell apoptosis. Dihydroethidium fluorescence was used to measure reactive oxygen species (ROS) in the lungs and A549 cells. ELISA was performed to detect TNF-α and IL-6 in the supernatant of bronchoalveolar lavage fluid (BALF) and A549 cells. RT-qPCR was done to measure the messenger RNA (mRNA) expression of TNF-α and IL-6 in the lungs and A549 cells. Western blotting assay was performed to detect the protein expression of phospho-JNK, total JNK, and cleaved caspase-3. Electrophoretic mobility shift assay was employed to detect the DNA binding activities of AP-1 and P-p65. JNK inhibitor SP600125 reduced JNK phosphorylation, downregulated cleaved caspase-3 protein level, decreased AP-1 transcriptional activity and ROS level, and reduced the transcription and expression of TNF-α and IL-6, which improved ALI and cell apoptosis after paraquat poisoning. Our results indicate that JNK/AP-1 mediates ALI as well as oxidative stress and inflammation deterioration secondary to paraquat poisoning.

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Authors and Affiliations

  1. Department of Emergency Medicine, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, People’s Republic of China

    Haitao Shen, Yu Wang, Xinfei Han, Qiang Zheng, Xue Cai, Honglei Zhang & Min Zhao

  2. Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, 110004, People’s Republic of China

    Na Wu

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  1. Haitao Shen
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  2. Na Wu
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  3. Yu Wang
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  4. Xinfei Han
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  5. Qiang Zheng
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  6. Xue Cai
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  7. Honglei Zhang
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  8. Min Zhao
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Correspondence to Min Zhao.

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The authors declare that they have no conflict of interest.

Funding

This study was funded by Science Foundation of Liaoning Education Department (grant numbers LK201633 and LK201603), Peking Union Medical Foundation-Ruiyi Emergency Medical Research Fund (grant number R2015021), and Provincial Natural Science Foundation of Liaoning (grant number 201602879).

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Shen, H., Wu, N., Wang, Y. et al. JNK Inhibitor SP600125 Attenuates Paraquat-Induced Acute Lung Injury: an In Vivo and In Vitro Study. Inflammation 40, 1319–1330 (2017). https://doi.org/10.1007/s10753-017-0575-8

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  • DOI: https://doi.org/10.1007/s10753-017-0575-8

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