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Paraquat induces lung alveolar epithelial cell apoptosis via Nrf-2-regulated mitochondrial dysfunction and ER stress.
Arch Toxicol. 2012 Oct; 86(10):1547-58.AT

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.

Authors+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22678742

Citation

Chen, Ya-Wen, et al. "Paraquat Induces Lung Alveolar Epithelial Cell Apoptosis Via Nrf-2-regulated Mitochondrial Dysfunction and ER Stress." Archives of Toxicology, vol. 86, no. 10, 2012, pp. 1547-58.
Chen YW, Yang YT, Hung DZ, et al. Paraquat induces lung alveolar epithelial cell apoptosis via Nrf-2-regulated mitochondrial dysfunction and ER stress. Arch Toxicol. 2012;86(10):1547-58.
Chen, Y. W., Yang, Y. T., Hung, D. Z., Su, C. C., & Chen, K. L. (2012). Paraquat induces lung alveolar epithelial cell apoptosis via Nrf-2-regulated mitochondrial dysfunction and ER stress. Archives of Toxicology, 86(10), 1547-58. https://doi.org/10.1007/s00204-012-0873-8
Chen YW, et al. Paraquat Induces Lung Alveolar Epithelial Cell Apoptosis Via Nrf-2-regulated Mitochondrial Dysfunction and ER Stress. Arch Toxicol. 2012;86(10):1547-58. PubMed PMID: 22678742.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Paraquat induces lung alveolar epithelial cell apoptosis via Nrf-2-regulated mitochondrial dysfunction and ER stress. AU - Chen,Ya-Wen, AU - Yang,Yuan-Ting, AU - Hung,Dong-Zong, AU - Su,Chin-Chuan, AU - Chen,Kuo-Liang, Y1 - 2012/06/08/ PY - 2012/02/17/received PY - 2012/05/16/accepted PY - 2012/6/9/entrez PY - 2012/6/9/pubmed PY - 2013/2/8/medline SP - 1547 EP - 58 JF - Archives of toxicology JO - Arch. Toxicol. VL - 86 IS - 10 N2 - 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. SN - 1432-0738 UR - https://www.unboundmedicine.com/medline/citation/22678742/Paraquat_induces_lung_alveolar_epithelial_cell_apoptosis_via_Nrf_2_regulated_mitochondrial_dysfunction_and_ER_stress_ L2 - https://dx.doi.org/10.1007/s00204-012-0873-8 DB - PRIME DP - Unbound Medicine ER -