Signaling pathways involved in paraquat-induced pulmonary toxicity: Molecular mechanisms and potential therapeutic drugs

Buendia, 2019, Burden of paraquat poisoning in the department of Antioquia, Colombia, BMC Pharmacol. Toxicol., 20, 11, 10.1186/s40360-019-0291-0 Gawarammana, 2011, Medical management of paraquat ingestion, Br. J. Clin. Pharmacol., 72, 745, 10.1111/j.1365-2125.2011.04026.x Dinis-Oliveira, 2008, Paraquat poisonings: mechanisms of lung toxicity, clinical features, and treatment, Crit. Rev. Toxicol., 38, 13, 10.1080/10408440701669959 Kelner, 1989, Paraquat resistance associated with reduced NADPH reductase in an energy-dependent paraquat-accumulating cell line, Arch. Biochem. Biophys., 274, 366, 10.1016/0003-9861(89)90450-5 Castello, 2007, Mitochondria are a major source of paraquat-induced reactive oxygen species production in the brain, J. Biol. Chem., 282, 14186, 10.1074/jbc.M700827200 Dinis-Oliveira, 2006, P-glycoprotein induction: an antidotal pathway for paraquat-induced lung toxicity, Free Radic. Biol. Med., 41, 1213, 10.1016/j.freeradbiomed.2006.06.012 Choi, 2007, Quantum dot-induced cell death involves Fas upregulation and lipid peroxidation in human neuroblastoma cells, J. Nanobiotechnol., 5, 1, 10.1186/1477-3155-5-1 Kurisaki, 1985, Lipid peroxidation in human paraquat poisoning, J. Toxicol. Sci., 10, 29, 10.2131/jts.10.29 Costantini, 1995, On the effects of paraquat on isolated mitochondria. Evidence that paraquat causes opening of the cyclosporin A-sensitive permeability transition pore synergistically with nitric oxide, Toxicology, 99, 77, 10.1016/0300-483X(94)02997-9 Song, 2019, Effect of endoplasmic reticulum calcium on paraquatinduced apoptosis of human lung type II alveolar epithelial A549 cells, Mol. Med. Rep., 20, 2419 Tokunaga, 1997, Determination of 8-hydroxy-deoxyguanosine formation in rat organs: assessment of paraquat-evoked oxidative DNA damage, Biochem. Mol. Biol. Int., 43, 73 Orito, 2004, Chymase is activated in the pulmonary inflammation and fibrosis induced by paraquat in hamsters, Tohoku J. Exp. Med., 203, 287, 10.1620/tjem.203.287 Toygar, 2015, The relation between oxidative stress, inflammation, and neopterin in the paraquat-induced lung toxicity, Hum Exp. Toxicol., 34, 198, 10.1177/0960327114533808 Nguyen, 2009, The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress, J Biol. Chem., 284, 13291, 10.1074/jbc.R900010200 Tonelli, 2018, Transcriptional Regulation by Nrf2, Antioxid. Redox Signal., 29, 1727, 10.1089/ars.2017.7342 Baird, 2014, Monitoring Keap1-Nrf2 interactions in single live cells, Biotechnol. Adv., 32, 1133, 10.1016/j.biotechadv.2014.03.004 Yuan, 2006, Butylated hydroxyanisole regulates ARE-mediated gene expression via Nrf2 coupled with ERK and JNK signaling pathway in HepG2 cells, Mol. Carcinog., 45, 841, 10.1002/mc.20234 Hayes, 2015, Dual regulation of transcription factor Nrf2 by Keap1 and by the combined actions of beta-TrCP and GSK-3, Biochem. Soc. Trans., 43, 611, 10.1042/BST20150011 Cullinan, 2003, Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival, Mol. Cell Biol., 23, 7198, 10.1128/MCB.23.20.7198-7209.2003 Rodriguez-Ramiro, 2012, Procyanidin B2 induces Nrf2 translocation and glutathione S-transferase P1 expression via ERKs and p38-MAPK pathways and protect human colonic cells against oxidative stress, Eur. J. Nutr., 51, 881, 10.1007/s00394-011-0269-1 Podder, 2012, Antioxidant effect of silymarin on paraquat-induced human lung adenocarcinoma A549 cell line, Food Chem.. Toxicol., 50, 3206, 10.1016/j.fct.2012.06.007 Kim, 2013, Cytoprotective effect of alpha-lipoic acid on paraquat-exposed human bronchial epithelial cells via activation of nuclear factor erythroid related factor-2 pathway, Biol. Pharm. Bull, 36, 802, 10.1248/bpb.b12-00977 Hu, 2019, Aspirin-triggered resolvin D1 alleviates paraquat-induced acute lung injury in mice, Life Sci.., 218, 38, 10.1016/j.lfs.2018.12.028 Shen, 2017, Chloroquine attenuates paraquat-induced lung injury in mice by altering inflammation, oxidative stress and fibrosis, Int. Immunopharmacol., 46, 16, 10.1016/j.intimp.2017.02.020 Liu, 2013, Inhibitory effects of rosiglitazone on paraquat-induced acute lung injury in rats, Acta. Pharmacol. Sin., 34, 1317, 10.1038/aps.2013.65 Tai, 2020, Rapamycin attenuates the paraquat-induced pulmonary fibrosis through activating Nrf2 pathway, J. Cell Physiol., 235, 1759, 10.1002/jcp.29094 Zhang, 2018, FGF21 attenuates pulmonary fibrogenesis through ameliorating oxidative stress in vivo and in vitro, Biomed. Pharmacother., 103, 1516, 10.1016/j.biopha.2018.03.100 Jeon, 2016, Cytoprotective Effect of Makgeolli Lees on Paraquat Induced Oxidative Stress in A549 Cells via Activation of NRF2 and Antioxidant Genes, J. Microbiol. Biotechnol., 26, 277, 10.4014/jmb.1510.10093 Cui, 2021, Arenaria kansuensis attenuates pulmonary fibrosis in mice via the activation of Nrf2 pathway and the inhibition of NF-kB/TGF-beta1/Smad2/3 pathway, Phytother. Res., 35, 974, 10.1002/ptr.6857 Kim, 2013, Antioxidant action of ellagic acid ameliorates paraquat-induced A549 cytotoxicity, Biol. Pharm. Bull, 36, 609, 10.1248/bpb.b12-00990 Liu, 2019, Ligustrazin increases lung cell autophagy and ameliorates paraquat-induced pulmonary fibrosis by inhibiting PI3K/Akt/mTOR and hedgehog signalling via increasing miR-193a expression, BMC Pulm. Med., 19, 35, 10.1186/s12890-019-0799-5 Liu, 2016, Radix puerariae extracts ameliorate paraquat-induced pulmonary fibrosis by attenuating follistatin-like 1 and nuclear factor erythroid 2p45-related factor-2 signalling pathways through downregulation of miRNA-21 expression, BMC Complement Altern. Med., 16, 11, 10.1186/s12906-016-0991-6 Zerin, 2013, Quercetin reduces oxidative damage induced by paraquat via modulating expression of antioxidant genes in A549 cells, J. Appl. Toxicol., 33, 1460, 10.1002/jat.2812 Li, 2016, Resveratrol protects mice from paraquat-induced lung injury: the important role of SIRT1 and NRF2 antioxidant pathways, Mol. Med. Rep., 13, 1833, 10.3892/mmr.2015.4710 Liu, 2016, Salvianolic acid B protects against paraquat-induced pulmonary injury by mediating Nrf2/Nox4 redox balance and TGF-beta1/Smad3 signaling, Toxicol. Appl. Pharmacol., 309, 111, 10.1016/j.taap.2016.08.004 Podder, 2013, Cytoprotective effect of bioactive sea buckthorn extract on paraquat-exposed A549 cells via induction of Nrf2 and its downstream genes, Mol. Med. Rep., 8, 1852, 10.3892/mmr.2013.1736 Li, 2018, Diterpene ginkgolides meglumine injection protects against paraquat-induced lung injury and pulmonary fibrosis in rats, Biomed. Pharmacother., 99, 746, 10.1016/j.biopha.2018.01.135 Mitchell, 2016, Signaling via the NFkappaB system, Wiley Interdiscip. Rev. Syst. Biol. Med., 8, 227, 10.1002/wsbm.1331 Wullaert, 2011, NF-kappaB in the regulation of epithelial homeostasis and inflammation, Cell Res., 21, 146, 10.1038/cr.2010.175 Hawiger, 2001, Innate immunity and inflammation: a transcriptional paradigm, Immunol. Res., 23, 99, 10.1385/IR:23:2-3:099 Hayden, 2008, Shared principles in NF-kappaB signaling, Cell, 132, 344, 10.1016/j.cell.2008.01.020 Chen, 2016, Protective Effect of Astragaloside IV Against Paraquat-Induced Lung Injury in Mice by Suppressing Rho Signaling, Inflammation, 39, 483, 10.1007/s10753-015-0272-4 El Assar, 2013, Oxidative stress and vascular inflammation in aging, Free Radic Biol Med, 65, 380, 10.1016/j.freeradbiomed.2013.07.003 Ali, 2004, Signal transduction via the NF-kappaB pathway: a targeted treatment modality for infection, inflammation and repair, Cell Biochem. Funct., 22, 67, 10.1002/cbf.1082 Panne, 2007, An atomic model of the interferon-beta enhanceosome, Cell, 129, 1111, 10.1016/j.cell.2007.05.019 Wang, 2022, The STING-IRF3 pathway contributes to paraquat-induced acute lung injury, Toxicol. Mech. Methods, 32, 145, 10.1080/15376516.2021.1974133 Wang, 2020, Inhibition of TBK1 by amlexanox attenuates paraquat-induced acute lung injury, Toxicology, 443, 10.1016/j.tox.2020.152555 Huang, 2016, Pyrrolidine dithiocarbamate attenuates paraquat-induced acute pulmonary poisoning in vivo via transforming growth factor beta1 and nuclear factor kappaB pathway interaction, Hum. Exp. Toxicol., 35, 1312, 10.1177/0960327116630351 Chen, 2013, Docosahexaenoic acid (DHA) attenuated paraquat induced lung damage in mice, Inhal Toxicol, 25, 9, 10.3109/08958378.2012.750405 Serhan, 2002, Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals, J. Exp. Med., 196, 1025, 10.1084/jem.20020760 Sun, 2007, Resolvin D1 and its aspirin-triggered 17R epimer. stereochemical assignments, anti-inflammatory properties, and enzymatic inactivation, J. Biol. Chem., 282, 9323, 10.1074/jbc.M609212200 Han, 2015, Natural antioxidant betanin protects rats from paraquat-induced acute lung injury interstitial pneumonia, Biomed Res. Int., 10.1155/2015/608174 Sun, 2011, The protective effect of C-phycocyanin on paraquat-induced acute lung injury in rats, Environ. Toxicol. Pharmacol., 32, 168 Ren, 2019, Curcumin relieves paraquatinduced lung injury through inhibiting the thioredoxin interacting protein/NLR pyrin domain containing 3mediated inflammatory pathway, Mol. Med. Rep., 20, 5032 SreeHarsha, 2020, Embelin impact on paraquat-induced lung injury through suppressing oxidative stress, inflammatory cascade, and MAPK/NF-kappaB signaling pathway, J. Biochem. Mol. Toxicol., 34, e22456, 10.1002/jbt.22456 Zhu, 2017, Porous Se@SiO2 nanospheres treated paraquat-induced acute lung injury by resisting oxidative stress, Int. J. Nanomed., 12, 7143, 10.2147/IJN.S143192 Amirshahrokhi, 2016, Carvedilol attenuates paraquat-induced lung injury by inhibition of proinflammatory cytokines, chemokine MCP-1, NF-kappaB activation and oxidative stress mediators, Cytokine, 88, 144, 10.1016/j.cyto.2016.09.004 Hu, 2017, Liver X Receptor Agonist TO901317 Attenuates Paraquat-Induced Acute Lung Injury through Inhibition of NF-kappaB and JNK/p38 MAPK Signal Pathways, Biomed Res. Int., 4652695 Liu, 2014, CB2 receptor activation ameliorates the proinflammatory activity in acute lung injury induced by paraquat, Biomed Res. Int. Wu, 2019, Metformin Activates the Protective Effects of the AMPK Pathway in Acute Lung Injury Caused by Paraquat Poisoning, Oxid. Med. Cell. Longevity, 1 Kelley, 2019, The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation, Int. J. Mol. Sci., 20, 3328, 10.3390/ijms20133328 Abais, 2015, Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector?, Antioxid. Redox Signal., 22, 1111, 10.1089/ars.2014.5994 Zhou, 2010, Thioredoxin-interacting protein links oxidative stress to inflammasome activation, Nat. Immunol., 11, 136, 10.1038/ni.1831 Ito, 2020, NLRP3 Inflammasome Activation in Lung Vascular Endothelial Cells Contributes to Intestinal Ischemia/Reperfusion-Induced Acute Lung Injury, J. Immunol., 205, 1393, 10.4049/jimmunol.2000217 Jones, 2014, The NLRP3 inflammasome is required for the development of hypoxemia in LPS/mechanical ventilation acute lung injury, Am. J. Respir. Cell Mol. Biol., 50, 270, 10.1165/rcmb.2013-0087OC Xiang, 2011, Hemorrhagic shock activation of NLRP3 inflammasome in lung endothelial cells, J. Immunol., 187, 4809, 10.4049/jimmunol.1102093 Liu, 2015, NLRP3 inflammasome activation is essential for paraquat-induced acute lung injury, Inflammation, 38, 433, 10.1007/s10753-014-0048-2 Jiang, 2018, Procyanidin B2 protects rats from paraquat-induced acute lung injury by inhibiting NLRP3 inflammasome activation, Immunobiology, 223, 555, 10.1016/j.imbio.2018.07.001 Fu, 2020, Polydatin relieves paraquat-induced human MRC-5 fibroblast injury through inhibiting the activation of the NLRP3 inflammasome, Ann. Transl. Med., 8, 765, 10.21037/atm-20-4570 Gong, 2018, Curcumin alleviates DSS-induced colitis via inhibiting NLRP3 inflammsome activation and IL-1beta production, Mol. Immunol., 104, 11, 10.1016/j.molimm.2018.09.004 Mansouri, 2011, Effects of grape seed proanthocyanidin extract on oxidative stress induced by diabetes in rat kidney, Iran. Biomed. J., 15, 100 Pahwa, 2016, Hyperglycemia Induces Toll-Like Receptor Activity Through Increased Oxidative Stress, Metab Syndr Relat Disord, 14, 239, 10.1089/met.2016.29006.pah Shen, 2017, Epigallocatechin-3-gallate alleviates paraquat-induced acute lung injury and inhibits upregulation of toll-like receptors, Life Sci., 170, 25, 10.1016/j.lfs.2016.11.021 Qian, 2015, Increased toll-like receptor 9 expression is associated with the severity of paraquat-induced lung injury in mice, Hum. Exp. Toxicol., 34, 430, 10.1177/0960327114542963 Liu, 2014, Toll-like receptor 4 implicated in acute lung injury induced by paraquat poisoning in mice, Int. J. Clin. Exp. Med., 7, 3392 Capelluto, 2012, Tollip: a multitasking protein in innate immunity and protein trafficking, Microbes Infect., 14, 140, 10.1016/j.micinf.2011.08.018 Zheng, 2021, Protective effect of toll-interacting protein overexpression against paraquat-induced lung injury in mice and A549 cells through inhibiting oxidative stress, inflammation, and NF-kappaB signaling pathway, Respir. Physiol. Neurobiol., 286, 10.1016/j.resp.2020.103600 Kim, 2006, Green tea extract inhibits paraquat-induced pulmonary fibrosis by suppression of oxidative stress and endothelin-l expression, Lung, 184, 287, 10.1007/s00408-005-2592-x Hernandez-Rodas, 2017, Supplementation with Docosahexaenoic Acid and Extra Virgin Olive Oil Prevents Liver Steatosis Induced by a High-Fat Diet in Mice through PPAR-alpha and Nrf2 Upregulation with Concomitant SREBP-1c and NF-kB Downregulation, Mol. Nutr. Food Res., 61, 10.1002/mnfr.201700479 Mateu, 2015, Cross-talk between TLR4 and PPARgamma pathways in the arachidonic acid-induced inflammatory response in pancreatic acini, Int. J. Biochem. Cell Biol., 69, 132, 10.1016/j.biocel.2015.10.022 Wang, 2011, PPARgamma agonist suppresses TLR4 expression and TNF-alpha production in LPS stimulated monocyte leukemia cells, Cell Biochem. Biophys., 60, 167, 10.1007/s12013-010-9136-6 Zhang, 2019, Rosiglitazone attenuates paraquat-induced lung fibrosis in rats in a PPAR gamma-dependent manner, Eur. J. Pharmacol., 851, 133, 10.1016/j.ejphar.2019.02.037 Li, 2016, Activating Peroxisome Proliferator-Activated Receptors (PPARs): a New Sight for Chrysophanol to Treat Paraquat-Induced Lung Injury, Inflammation, 39, 928, 10.1007/s10753-016-0326-2 Malekinejad, 2014, Atorvastatin attenuates the paraquat-induced pulmonary inflammation via PPARgamma receptors: a new indication for atorvastatin, Pestic. Biochem. Physiol., 114, 79, 10.1016/j.pestbp.2014.06.011 Alizadeh-Tabrizi, 2017, Atorvastatin protected from paraquat-induced cytotoxicity in alveolar macrophages via down-regulation of TLR-4, Environ. Toxicol. Pharmacol., 49, 8, 10.1016/j.etap.2016.11.011 Mccubrey, 2006, Reactive oxygen species-induced activation of the MAP kinase signaling pathways, Antioxid. Redox Signal., 8, 1775, 10.1089/ars.2006.8.1775 Kim, 2010, Pathological roles of MAPK signaling pathways in human diseases, Biochim. Biophys. Acta, Biomembr., 1802, 396, 10.1016/j.bbadis.2009.12.009 Torii, 2006, ERK MAP kinase in G cell cycle progression and cancer, Cancer Sci., 97, 697, 10.1111/j.1349-7006.2006.00244.x Hitti, 2006, Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element, Mol. Cell. Biol., 26, 2399, 10.1128/MCB.26.6.2399-2407.2006 Son, 2011, Mitogen-Activated Protein Kinases and Reactive Oxygen Species: how can ROS activate MAPK Pathways?, J. Signal Transduct, 10.1155/2011/792639 De Chiara, 2006, Bcl-2 Phosphorylation by p38 MAPK: identification of target sites and biologic consequences, J. Biol. Chem., 281, 21353, 10.1074/jbc.M511052200 Park, 2014, ROS-mediated JNK/p38-MAPK activation regulates Bax translocation in Sorafenib-induced apoptosis of EBV-transformed B cells, Int. J. Oncol., 44, 977, 10.3892/ijo.2014.2252 Cui, 2019, Ghrelin ameliorates A549 cell apoptosis caused by paraquat via p38-MAPK regulated mitochondrial apoptotic pathway, Toxicology, 426, 10.1016/j.tox.2019.152267 Zhang, 2020, Klotho Alleviates Lung Injury Caused by Paraquat via Suppressing ROS/P38 MAPK-Regulated Inflammatory Responses and Apoptosis, Oxid. Med. Cell Longev, 1854206 Tang, 2014, Anti-inflammatory effects of Reduning Injection on lipopolysaccharide-induced acute lung injury of rats, Chin J. Integr. Med., 20, 591, 10.1007/s11655-014-1758-x Jiang, 2019, Reduning injection ameliorates paraquat-induced acute lung injury by regulating AMPK/MAPK/NF-kappaB signaling, J. Cell. Biochem., 120, 12713, 10.1002/jcb.28540 Garcia, 2017, AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance, Mol. Cell, 66, 789, 10.1016/j.molcel.2017.05.032 Mihaylova, 2011, The AMPK signalling pathway coordinates cell growth, autophagy and metabolism, Nat. Cell Biol., 13, 1016, 10.1038/ncb2329 Zhang, 2017, The alleviative effects of metformin for lipopolysaccharide-induced acute lung injury rat model and its underlying mechanism, Saudi Pharm. J., 25, 666, 10.1016/j.jsps.2017.05.001 Gamad, 2018, Metformin alleviates bleomycin-induced pulmonary fibrosis in rats: pharmacological effects and molecular mechanisms, Biomed. Pharmacother., 97, 1544, 10.1016/j.biopha.2017.11.101 Wu, 2019, Metformin Activates the Protective Effects of the AMPK Pathway in Acute Lung Injury Caused by Paraquat Poisoning, Oxid Med. Cell Longev., 1709718 Deng, 2019, RhoA/ROCK pathway: implication in osteoarthritis and therapeutic targets, Am. J. Transl. Res., 11, 5324 Amano, 2010, Rho-kinase/ROCK: a key regulator of the cytoskeleton and cell polarity, Cytoskeleton (Hoboken), 67, 545, 10.1002/cm.20472 Geng, 2012, Lysophosphatidic acid increases proximal tubule cell secretion of profibrotic cytokines PDGF-B and CTGF through LPA2- and Galphaq-mediated Rho and alphavbeta6 integrin-dependent activation of TGF-beta, Am. J. Pathol., 181, 1236, 10.1016/j.ajpath.2012.06.035 Citi, 2014, Epithelial junctions and Rho family GTPases: the zonular signalosome, Small GTPases, 5, 1, 10.4161/21541248.2014.973760 Abedi, 2020, Acute lung injury: the therapeutic role of Rho kinase inhibitors, Pharmacol. Res., 155, 10.1016/j.phrs.2020.104736 Zhang, 2018, Protective Effects of a Rho Kinase Inhibitor on Paraquat-Induced Acute Lung Injuries in Rats, Inflammation, 41, 2171, 10.1007/s10753-018-0860-1 Luo, 2004, Astragaloside IV protects against ischemic brain injury in a murine model of transient focal ischemia, Neurosci. Lett., 363, 218, 10.1016/j.neulet.2004.03.036 Ersahin, 2015, The PI3K/AKT/mTOR interactive pathway, Mol. BioSyst., 11, 1946, 10.1039/C5MB00101C Gui, 2018, Leptin promotes pulmonary fibrosis development by inhibiting autophagy via PI3K/Akt/mTOR pathway, Biochem. Biophys. Res. Commun., 498, 660, 10.1016/j.bbrc.2018.03.039 Wang, 2022, Targeting PI3K/AKT signaling for treatment of idiopathic pulmonary fibrosis, Acta. Pharm. Sin. B, 12, 18, 10.1016/j.apsb.2021.07.023 Li, 2021, Lipoxin A4 protects against paraquatinduced acute lung injury by inhibiting the TLR4/MyD88mediated activation of the NFkappaB and PI3K/AKT pathways, Int. J. Mol. Med., 47, 86, 10.3892/ijmm.2021.4919 Jiang, 2021, Fluorofenidone attenuates paraquatinduced pulmonary fibrosis by regulating the PI3K/Akt/mTOR signaling pathway and autophagy, Mol. Med. Rep., 23, 405, 10.3892/mmr.2021.12044 Ahmed, 2019, Protective effects of febuxostat against paraquat-induced lung toxicity in rats: Impact on RAGE/PI3K/Akt pathway and downstream inflammatory cascades, Life Sci., 221, 56, 10.1016/j.lfs.2019.02.007 Madrid, 2001, Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38, J. Biol. Chem., 276, 18934, 10.1074/jbc.M101103200 Walton, 2017, Targeting TGF-beta Mediated SMAD signaling for the prevention of fibrosis, Front. Pharmacol., 8, 461, 10.3389/fphar.2017.00461 Han, 2015, Involvement of epithelial-to-mesenchymal transition and associated transforming growth factor-beta/Smad signaling in paraquat-induced pulmonary fibrosis, Mol. Med. Rep., 12, 7979, 10.3892/mmr.2015.4454 Zeng, 2015, Inhibition of HMGB1 release via salvianolic acid B-mediated SIRT1 up-regulation protects rats against non-alcoholic fatty liver disease, Sci. Rep., 5, 16013, 10.1038/srep16013 Tang, 2014, Salvianolic acid B protects human endothelial progenitor cells against oxidative stress-mediated dysfunction by modulating Akt/mTOR/4EBP1, p38 MAPK/ATF2, and ERK1/2 signaling pathways, Biochem. Pharmacol., 90, 34, 10.1016/j.bcp.2014.04.008 Guo, 2012, Wnt/beta-catenin signaling: a promising new target for fibrosis diseases, Physiol. Res., 61, 337, 10.33549/physiolres.932289 Liu, 2021, Noncanonical Wnt signaling promotes myofibroblast differentiation in pulmonary fibrosis, Am. J. Respir. Cell Mol. Biol., 65, 489, 10.1165/rcmb.2020-0499OC Sun, 2020, Paraquat induces pulmonary fibrosis through Wnt/beta-catenin signaling pathway and myofibroblast differentiation, Toxicol. Lett., 333, 170, 10.1016/j.toxlet.2020.08.004 Saha, 2020, An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation, Molecules, 25, 5474, 10.3390/molecules25225474 Liu, 2008, NF-kappaB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK, Biochim. Biophys. Acta, Biomembr., 1783, 713, 10.1016/j.bbamcr.2008.01.002 Jhang, 2017, The role of Nrf2 in NLRP3 inflammasome activation, Cell. Mol. Immunol., 14, 1011, 10.1038/cmi.2017.114 Polvani, 2012, PPARgamma and Oxidative Stress: Con(beta) Catenating NRF2 and FOXO, PPAR Res, 10.1155/2012/641087 Lee, 2017, Collaborative Power of Nrf2 and PPARgamma Activators against Metabolic and Drug-Induced Oxidative Injury, Oxid Med Cell Longev, 1378175 Reddy, 2010, Nrf2 and PPAR{gamma}: PPARtnering against oxidant-induced lung injury, Am. J. Respir. Crit. Care Med., 182, 134, 10.1164/rccm.201004-0457ED Liu, 2021, Regulation of Nrf2 by phosphorylation: Consequences for biological function and therapeutic implications, Free Radic Biol Med, 168, 129, 10.1016/j.freeradbiomed.2021.03.034 Sun, 2009, Phosphorylation of Nrf2 at multiple sites by MAP kinases has a limited contribution in modulating the Nrf2-dependent antioxidant response, PLoS ONE, 4, e6588, 10.1371/journal.pone.0006588 Joo, 2016, AMPK Facilitates Nuclear Accumulation of Nrf2 by Phosphorylating at Serine 550, Mol. Cell. Biol., 36, 1931, 10.1128/MCB.00118-16 Yin, 2015, Toll-Like Receptor Signaling Induces Nrf2 Pathway Activation through p62-Triggered Keap1 Degradation, Mol. Cell. Biol., 35, 2673, 10.1128/MCB.00105-15 Mohan, 2018, Crosstalk of toll-like receptors signaling and Nrf2 pathway for regulation of inflammation, Biomed. Pharmacother., 108, 1866, 10.1016/j.biopha.2018.10.019 Reddy, 2015, PI3K-AKT Signaling via Nrf2 Protects against Hyperoxia-Induced Acute Lung Injury, but Promotes Inflammation Post-Injury Independent of Nrf2 in Mice, PLoS ONE, 10, e0129676, 10.1371/journal.pone.0129676 Korswagen, 2006, Regulation of the Wnt/beta-catenin pathway by redox signaling, Dev. Cell, 10, 687, 10.1016/j.devcel.2006.05.007 Rao, 2022, Macrophage nuclear factor erythroid 2-related factor 2 deficiency promotes innate immune activation by tissue inhibitor of metalloproteinase 3-mediated RhoA/ROCK pathway in the ischemic liver, Hepatology, 75, 1429, 10.1002/hep.32184 Hu, 2018, New insights into TGF-beta/Smad signaling in tissue fibrosis, Chem. Biol. Interact., 292, 76, 10.1016/j.cbi.2018.07.008 Guan, 2018, NF-E2-Related Factor 2 Suppresses Intestinal Fibrosis by Inhibiting Reactive Oxygen Species-Dependent TGF-beta1/SMADs Pathway, Dig. Dis. Sci., 63, 366, 10.1007/s10620-017-4710-z Harchegani, 2017, Cromolyn Sodium Attenuates Paraquat-Induced Lung Injury by Modulation of Proinflammatory Cytokines, Drug Res (Stuttg), 67, 283, 10.1055/s-0042-123711 Lee, 2008, Protective effects of ethyl pyruvate treatment on paraquat-intoxicated rats, Hum. Exp. Toxicol., 27, 49, 10.1177/0960327108088976 Lin, 2006, Repeated pulse of methylprednisolone and cyclophosphamide with continuous dexamethasone therapy for patients with severe paraquat poisoning, Crit. Care Med., 34, 368, 10.1097/01.CCM.0000195013.47004.A8 Chen, 2002, Combined methylprednisolone and dexamethasone therapy for paraquat poisoning, Crit. Care Med., 30, 2584, 10.1097/00003246-200211000-00030 Lin, 2011, Improved survival in severe paraquat poisoning with repeated pulse therapy of cyclophosphamide and steroids, Intensive Care Med., 37, 1006, 10.1007/s00134-010-2127-7 Gawarammana, 2018, High-dose immunosuppression to prevent death after paraquat self-poisoning - a randomised controlled trial, Clin. Toxicol. (Phila), 56, 633, 10.1080/15563650.2017.1394465 Drault, 1999, Massive paraquat poisoning. favorable course after treatment with n-acetylcysteine and early hemodialysis, Ann. Fr. Anesth. Reanim., 18, 534, 10.1016/S0750-7658(99)80127-0 Moon, 2011, The efficacy of high doses of vitamin C in patients with paraquat poisoning, Hum. Exp. Toxicol., 30, 844, 10.1177/0960327110385633 Kim, 2010, Effect of glutathione administration on serum levels of reactive oxygen metabolites in patients with paraquat intoxication: a pilot study, Korean J. Intern. Med., 25, 282, 10.3904/kjim.2010.25.3.282 Su, 2021, Study on the efficacy and safety of ambroxol combined with methylprednisolone in patients with acute lung injury, Biomed Res. Int., 5771101 Yi, 2019, Retrospective study of clinical features and prognosis of edaravone in the treatment of paraquat poisoning, Med. (Baltimore), 98, e15441, 10.1097/MD.0000000000015441 Ren, 2021, Inhibitory effect of pirfenidone on pulmonary fibrosis in patients with acute paraquat poisoning, Am. J. Transl. Res., 13, 13192 Liu, 2019, Protective mechanism of 1-methylhydantoin against lung injury induced by paraquat poisoning, PLoS ONE, 14, e0222521, 10.1371/journal.pone.0222521 Liu, 2018, Apigenin reverses lung injury and immunotoxicity in paraquat-treated mice, Int. Immunopharmacol., 65, 531, 10.1016/j.intimp.2018.10.046 Li, 2015, DNaseI protects against Paraquat-induced acute lung injury and pulmonary fibrosis mediated by mitochondrial DNA, Biomed Res. Int. Shopova, 2009, Protective effects of a superoxide dismutase/catalase mimetic compound against paraquat pneumotoxicity in rat lung, Respirology, 14, 504, 10.1111/j.1440-1843.2009.01531.x Javad-Mousavi, 2016, Protective effect of Berberis vulgaris fruit extract against Paraquat-induced pulmonary fibrosis in rats, Biomed. Pharmacother., 81, 329, 10.1016/j.biopha.2016.04.027 Sun, 2018, Treatment of Paraquat-Induced Lung Injury With an Anti-C5a Antibody: potential Clinical Application, Crit. Care Med., 46, e419, 10.1097/CCM.0000000000002950 El-Aarag, 2019, Melittin exerts beneficial effects on paraquat-induced lung injuries in mice by modifying oxidative stress and apoptosis, Molecules, 24, 1498, 10.3390/molecules24081498 Chen, 2013, Protective effects of naringin against paraquat-induced acute lung injury and pulmonary fibrosis in mice, Food Chem. Toxicol., 58, 133, 10.1016/j.fct.2013.04.024 Khalighi, 2016, Perfluorocarbon attenuates inflammatory cytokines, oxidative stress and histopathologic changes in paraquat-induced acute lung injury in rats, Environ. Toxicol. Pharmacol., 42, 9, 10.1016/j.etap.2015.12.002 Chang, 2009, Pyrrolidine dithiocarbamate attenuates paraquat-induced lung injury in rats, J. Biomed. Biotechnol., 10.1155/2009/619487 Park, 2010, Protective effect of quercetin against paraquat-induced lung injury in rats, Life Sci., 87, 181, 10.1016/j.lfs.2010.06.011 Omura, 2013, Sodium tauroursodeoxycholate prevents paraquat-induced cell death by suppressing endoplasmic reticulum stress responses in human lung epithelial A549 cells, Biochem. Biophys. Res. Commun., 432, 689, 10.1016/j.bbrc.2013.01.131 Pourgholamhossein, 2016, Thymoquinone effectively alleviates lung fibrosis induced by paraquat herbicide through down-regulation of pro-fibrotic genes and inhibition of oxidative stress, Environ. Toxicol. Pharmacol., 45, 340, 10.1016/j.etap.2016.06.019 Xie, 2018, The KCa3.1 blocker TRAM-34 inhibits proliferation of fibroblasts in paraquat-induced pulmonary fibrosis, Toxicol. Lett., 295, 408, 10.1016/j.toxlet.2018.07.020 Wang, 2016, Lysyl oxidase promotes epithelial-to-mesenchymal transition during paraquat-induced pulmonary fibrosis, Mol. BioSyst., 12, 499, 10.1039/C5MB00698H Cho, 2011, Protective effect of 4,4'-diaminodiphenylsulfone against paraquat-induced mouse lung injury, Exp. Mol. Med., 43, 525, 10.3858/emm.2011.43.9.060 Zhi, 2011, Protective effect of ambroxol against paraquat-induced pulmonary fibrosis in rats, Intern. Med., 50, 1879, 10.2169/internalmedicine.50.5407 Du, 2018, Atorvastatin attenuates paraquat poisoning-induced epithelial-mesenchymal transition via downregulating hypoxia-inducible factor-1 alpha, Life Sci., 213, 126, 10.1016/j.lfs.2018.10.026 Xu, 2016, Chloroquine rescues A549 cells from paraquat-induced death, Drug Chem. Toxicol., 39, 167, 10.3109/01480545.2015.1063063 Mirzaee, 2019, Diosmin ameliorative effects on oxidative stress and fibrosis in paraquat-induced lung injury in mice, Environ. Sci. Pollut. Res. Int., 26, 36468, 10.1007/s11356-019-06572-2 Zhi, 2011, Edaravone, a novel antidote against lung injury and pulmonary fibrosis induced by paraquat?, Int. Immunopharmacol., 11, 96, 10.1016/j.intimp.2010.10.012 Qian, 2014, FTY720 attenuates paraquat-induced lung injury in mice, Int. Immunopharmacol., 21, 426, 10.1016/j.intimp.2014.05.025 Guo, 2015, Losartan attenuates paraquat-induced pulmonary fibrosis in rats, Hum. Exp. Toxicol., 34, 497, 10.1177/0960327114543840 Tian, 2013, Methylene blue protects against paraquat-induced acute lung injury in rats, Int. Immunopharmacol., 17, 309, 10.1016/j.intimp.2013.06.022 Amirshahrokhi, 2013, Effect of methylsulfonylmethane on paraquat-induced acute lung and liver injury in mice, Inflammation, 36, 1111, 10.1007/s10753-013-9645-8 Ahmed, 2009, Protective effect of montelukast on paraquat-induced lung toxicity in rats, Biosci. Trends, 3, 63 Yeh, 2006, Protective effects of N-acetylcysteine treatment post acute paraquat intoxication in rats and in human lung epithelial cells, Toxicology, 223, 181, 10.1016/j.tox.2006.03.019 Pourgholamhossein, 2018, Pirfenidone protects against paraquat-induced lung injury and fibrosis in mice by modulation of inflammation, oxidative stress, and gene expression, Food Chem. Toxicol., 112, 39, 10.1016/j.fct.2017.12.034 Shao, 2015, Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice, J. Zhejiang Univ. Sci. B, 16, 52, 10.1631/jzus.B1400229 Zhao, 2015, Silymarin attenuates paraquat-induced lung injury via Nrf2-mediated pathway in vivo and in vitro, Clin. Exp. Pharmacol. Physiol., 42, 988, 10.1111/1440-1681.12448 Dinis-Oliveira, 2007, Sodium salicylate prevents paraquat-induced apoptosis in the rat lung, Free Radic. Biol. Med., 43, 48, 10.1016/j.freeradbiomed.2007.03.014 Kim, 2012, Antioxidant effects of selenium on lung injury in paraquat intoxicated rats, Clin. Toxicol. (Phila), 50, 749, 10.3109/15563650.2012.708418 Li, 2019, Protective Effect of Taurine on Paraquat-Induced Lung Epithelial Cell Injury, Adv. Exp. Med. Biol., 1155, 739, 10.1007/978-981-13-8023-5_64 Rodrigues da Silva, 2018, Beneficial effects of ascorbic acid to treat lung fibrosis induced by paraquat, PLoS ONE, 13, e0205535, 10.1371/journal.pone.0205535 Liu, 2014, Protective effect of Xuebijing injection on paraquat-induced pulmonary injury via down-regulating the expression of p38 MAPK in rats, BMC Complement Altern. Med., 14, 498, 10.1186/1472-6882-14-498 Liu, 2011, Consumption of hydrogen water reduces paraquat-induced acute lung injury in rats, J. Biomed. Biotechnol., 2011, 10.1155/2011/305086 Kaldirim, 2014, Ozone therapy ameliorates paraquat-induced lung injury in rats, Exp. Biol. Med. (Maywood), 239, 1699, 10.1177/1535370214543060