Association of <i>Nrf2</i> Polymorphism Haplotypes with Acute Lung Injury Phenotypes in Inbred Strains of Mice

Cho, Hye‐Youn; Jedlicka, Anne; Gladwell, Wesley; Marzec, Jacqui; McCaw, Zachary R.; Bienstock, Rachelle J.; Kleeberger, Steven R.

doi:10.1089/ars.2014.5942

Cited by 30 publications

(35 citation statements)

References 59 publications

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“…Nrf2 antioxidant responses occur after exposure to other liver toxins including aflatoxin (Kensler et al 2014; Merrick et al 2012; Singh et al 2015) and carbon tetrachloride (Chen et al 2014), and are found in other organ toxicities including in the lung (Cho et al 2015) and nasal cavity (Dunnick et al 2015). …”

Section: Discussionmentioning

confidence: 99%

Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats

et al. 2016

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N,N-dimethyl-p-toluidine (DMPT), an accelerant for methyl methacrylate monomers in medical devices, was a liver carcinogen in male and female F344/N rats and B6C3F1 mice in a 2-year oral exposure study. p-Toluidine, a structurally-related chemical, was a liver carcinogen in mice but not in rats in an 18-month feed exposure study. In this current study, liver transcriptomic data was used to characterize mechanisms in DMPT and p-toluidine liver toxicity and for conducting benchmark dose (BMD) analysis. Male F344/N rats were exposed orally to DMPT or p-toluidine (0, 1, 6, 20, 60 or 120 mg/kg/day) for 5-days. The liver was examined for lesions and transcriptomic alterations. Both chemicals caused mild hepatic toxicity at 60 and 120 mg/kg and dose-related transcriptomic alterations in the liver. There were 511 liver transcripts differentially expressed for DMPT and 354 for p-toluidine at 120 mg/kg/day (false discovery rate threshold of 5%). The liver transcriptomic alterations were characteristic of an anti-oxidative damage response (activation of the Nrf2 pathway) and hepatic toxicity. The top cellular processes in gene ontology (GO) categories altered in livers exposed to DMPT or p-toluidine were used for BMD calculations. The lower confidence bound benchmark doses (BMDL) for these chemicals were 2 mg/kg/day for DMPT and 7 mg/kg/day for p-toluidine. These studies show the promise of using 5-day target organ transcriptomic data to identify chemical-induced molecular changes that can serve as markers for preliminary toxicity risk assessment.

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Section: Discussionmentioning

confidence: 99%

Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats

et al. 2016

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“…Therefore, the expression of intra and extracellular antioxidants in airway epithelial cells and fluids is prominent. Numerous in vitro and in vivo studies have demonstrated the importance of Nrf2 activation to decrease oxidative stress and inflammation in conditions such as pulmonary fibrosis, cystic fibrosis, emphysema, COPD, ALI, asthma, bronchopulmonary dysplasia, and airway infections (Cho, Kleeberger 2015; Chan, Kan 1999). In the particular context of ALI/ARDS, the benefits of both basal and induced Nrf2 signaling have been investigated in various cellular and mouse models, as well as in human patient samples, as will be discussed below.…”

Section: The Protective Role Of Nrf2 In Alimentioning

confidence: 99%

“…2015a; Cordova et al 2011; Cho et al 2015c). In a hyperoxia-induced ALI mouse model, the functional effects of promoter and coding SNPs revealed that some haplotypes characteristic to certain inbred mouse strains confer increased susceptibility to hyperoxia due to lower Nrf2 mRNA expression and compromised protein function (Cho et al 2015a). These studies will help identify populations at greater risk of developing ALI that would benefit from more effective chemopreventive interventions through Nrf2 upregulation.…”

Section: The Protective Role Of Nrf2 In Alimentioning

confidence: 99%

“…Additionally, unresolved oxidative stress and inflammation in Nrf2 −/− mice increased apoptosis in sublethal hyperoxic exposure (48 h) and compromised tissue repair (Reddy et al 2009a). These results indicate that Nrf2 has additional roles that go beyond the resolution of oxidative stress, including the regulation of inflammation and tissue remodeling factors (Cho, Kleeberger 2015). Currently, it is unknown if Nrf2 modulates these processes directly or indirectly, so further detailed mechanistic studies are needed to elucidate these Nrf2-dependent effects.…”

Section: The Protective Role Of Nrf2 In Alimentioning

confidence: 99%

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Role of Nrf2 and Autophagy in Acute Lung Injury

et al. 2016

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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the clinical manifestations of severe lung damage and respiratory failure. Characterized by severe inflammation and compromised lung function, ALI/ARDS result in very high mortality of affected individuals. Currently, there are no effective treatments for ALI/ARDS, and ironically, therapies intended to aid patients (specifically mechanical ventilation, MV) may aggravate the symptoms. Key events contributing to the development of ALI/ARDS are: increased oxidative and proteotoxic stresses, unresolved inflammation, and compromised alveolar-capillary barrier function. Since the airways and lung tissues are constantly exposed to gaseous oxygen and airborne toxicants, the bronchial and alveolar epithelial cells are under higher oxidative stress than other tissues. Cellular protection against oxidative stress and xenobiotics is mainly conferred by Nrf2, a transcription factor that promotes the expression of genes that regulate oxidative stress, xenobiotic metabolism and excretion, inflammation, apoptosis, autophagy, and cellular bioenergetics. Numerous studies have demonstrated the importance of Nrf2 activation in the protection against ALI/ARDS, as pharmacological activation of Nrf2 prevents the occurrence or mitigates the severity of ALI/ARDS. Another promising new therapeutic strategy in the prevention and treatment of ALI/ARDS is the activation of autophagy, a bulk protein and organelle degradation pathway. In this review, we will discuss the strategy of concerted activation of Nrf2 and autophagy as a preventive and therapeutic intervention to ameliorate ALI/ARDS.

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“…The Nrf2 polymorphism contributes to poor prognosis in cancers, including cholangiocarcinoma [65], lung cancer [66], and breast cancer [67]. It also contributed to diseases, such as increasing the risk of acute lung injury [68,69] as well as blood pressure and cardiovascular mortality in patients with hemodialysis [70].…”

Section: Nrf2 Activation In Tumorsmentioning

confidence: 99%

Nrf2 Contributes to the Poor Prognosis and Chemoresistance

Syu¹,

Chi²,

Kung³

2016

A Master Regulator of Oxidative Stress - The Transcription Factor Nrf2

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With the increasing incidence of human cancer and continued diiculty in treating metastatic tumors, there is an urgent need to identify biomarkers for tumors with poor outcome and novel therapeutic targets. Many therapeutic targets have been found in recent years. One promising biomarker and therapeutic target that is valuable for human tumor is nuclear factor erythroid 2-related factor 2 NFE2L2, Nrf2 . In this chapter, we will discuss the regulatory mechanisms and conlicting roles of Nrf2 during diferent stages of tumor development as well as its involvement in the drug resistance and hypoxia-induced chemoresistance. We will also discuss various positive and negative modulators of Nrf2 as reference to their potential utility as study tools and leads for further clinical development.

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Association of Nrf2 Polymorphism Haplotypes with Acute Lung Injury Phenotypes in Inbred Strains of Mice

Cited by 30 publications

References 59 publications

Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats

Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats

Role of Nrf2 and Autophagy in Acute Lung Injury

Nrf2 Contributes to the Poor Prognosis and Chemoresistance

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