alexa Paraquat induces lung alveolar epithelial cell apoptosis via Nrf-2-regulated mitochondrial dysfunction and ER stress.


Journal of Environmental & Analytical Toxicology

Author(s): Chen YW, Yang YT, Hung DZ, Su CC, Chen KL

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Abstract Paraquat (1,1'-dimethyl-4,4'-bipyridinium chloride; PQ) is widely and commonly used as a herbicides in the world. PQ has been reported to be a major hazard because it causes lung injury. However, the molecular mechanisms underlying PQ-induced lung toxicity still need to be elucidated. Here, we found that PQ significantly decreases cell viability, increases sub-G1 hypodiploids DNA contents and caspase 3/7 activity in lung alveolar epithelial cell-derived L2 cells, which also caused mitochondrial dysfunction, and decreased the mRNA expression of Bcl-2 and increased that of Bax, Bak, and p53. Moreover, the protein expressions of Bax and Bak were increased in PQ-treated cells. In addition, when PQ was exposed to L2 cells, the expressions of ER stress-related signaling genes (including Grp78, CHOP, and caspase-12 mRNA) and proteins (including phospho-eIF-2α, CHOP, Grp78, calpain I and -II, and caspase-12) were significantly increased. PQ also decreased the protein expressions of pro-caspase-9/7/3. Next, we investigated the role of Nrf-2 in PQ-induced alveolar epithelial cell toxicity. In L2 cells, PQ induced Nrf-2 translocation from the cytosol to the nucleus. Cells transfected with Nrf-2 siRNA significantly reversed the PQ-induced toxicity, including depolarization of MMP, increased the Bax, Bak, p53 mRNAs expression, decreased the Bcl-2 mRNA expression, increased the caspase 3/7 activity, Grp78, CHOP, and caspase-12 mRNAs and protein expression, and decreased that of pro-caspase-3. Taken together, these results suggest that Nrf-2-regulated mitochondria and ER stress-related pathways are involved in the PQ-induced alveolar epithelial cell injury. This article was published in Arch Toxicol and referenced in Journal of Environmental & Analytical Toxicology

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