Paraquat induces lung alveolar epithelial cell apoptosis via Nrf-2-regulated mitochondrial dysfunction and ER stress.
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.
Department of Physiology, and Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, No. 91 Hsueh-Shih Road, Taichung, 40402, Taiwan, ywc@mail.cmu.edu.tw.
Ya-Wen
YW
Chen
Yuan-Ting
YT
Yang
Dong-Zong
DZ
Hung
Chin-Chuan
CC
Su
Kuo-Liang
KL
Chen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006540:Herbicides / Q000633:toxicity; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010269:Paraquat / Q000633:toxicity*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
D006540:Herbicides; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D034741:RNA, Small Interfering; D010269:Paraquat