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Inflammation. 2019 Feb 8. doi: 10.1007/s10753-018-00956-1. [Epub ahead of print]

High-Dose Paraquat Induces Human Bronchial 16HBE Cell Death and Aggravates Acute Lung Intoxication in Mice by Regulating Keap1/p65/Nrf2 Signal Pathway.

Author information

1
Department of Internal Medicine Ward 5, Guangdong Provincial Corps Hospital of Chinese People's Armed Police Forces, Guangzhou Medical University, Guangzhou, Guangdong, 510507, People's Republic of China.
2
Department of Pulmonary and Critical Care Medicine, The People Hospital of Yuxi City, Yuxi, China.
3
Department of Clinical Laboratory, Yunnan Molecular Diagnostic Center, The 2nd Affiliated Hospital of Kunming Medical University, Dianmian Road, Kunming, Yunnan, China.
4
Department of Respiratory, The 2nd Affiliated Hospital of Kunming Medical University, Dianmian Road 374, Kunming, 650101, Yunnan, China.
5
Department of Respiratory, The 2nd Affiliated Hospital of Kunming Medical University, Dianmian Road 374, Kunming, 650101, Yunnan, China. zhangtao08265@163.com.

Abstract

Paraquat (PQ) intoxication seriously endangers human beings' health, however, the underlying mechanisms are still unclear. Here we found that PQ inhibits human bronchial 16HBE cell proliferation and promotes cell apoptosis, necrosis as well as ROS generation in a dose dependent manner. Of note, low-dose PQ (50 μM) induces cell autophagy, increases Nrf2 as well as p65 levels and has little impacts on Keap1, while high-dose PQ (500 μM) inhibits autophagy, upregulates Keap1 as well as downregulates p65 and Nrf2. In addition, we verified that p65 overexpression increases Nrf2 and its downstream targets in 16HBE cells, which are reversed by synergistically knocking down Nrf2. Our further results showed that high-dose PQ's effects on cell proliferation, apoptosis, ROS levels and autophagy are reversed by p65 overexpression. Besides, the protective effects of overexpressed p65 on high-dose PQ (500 μM) treated 16HBE cells are abrogated by synergistically knocking down Nrf2. In vivo experiments also showed that high-dose PQ promotes inflammatory cytokines secretion, lung fibrosis and cell apoptosis, inhibits cell proliferation in mice models by regulating Keap1/p65/Nrf2 signal pathway. Therefore, we concluded that high-dose PQ (500 μM) inhibits 16HBE cell proliferation and autophagy, promotes cell death and mice lung fibrosis by regulating Keap1/p65/Nrf2 signal pathway.

KEYWORDS:

Keap1; Lung fibrosis; Nrf2; Paraquat; p65

PMID:
30734183
DOI:
10.1007/s10753-018-00956-1

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