Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice
By T. Rangasamy, Jia Guo, W. Mitzner, J. Roman, Anju Singh, A. Fryer, Masayuki Yamamoto, T. Kensler, R. Tuder, S. Georas and 1 more. Journal of Experimental Medicine, 2005
623 citations recorded by the source corpus.
Oxidative stress has been postulated to play an important role in the pathogenesis of asthma; although a defect in antioxidant responses has been speculated to exacerbate asthma severity, this has been difficult to demonstrate with certainty. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive basic leucine zipper transcription factor that is involved in the transcriptional regulation of many antioxidant genes. We show that disruption of the Nrf2 gene leads to severe allergen-driven airway inflammation and hyperresponsiveness in mice. Enhanced asthmatic response as a result of ovalbumin sensitization and challenge in Nrf2-disrupted mice was associated with more pronounced mucus cell hyperplasia and infiltration of eosinophils into the lungs than seen in wild-type littermates. Nrf2 disruption resulted in an increased expression of the T helper type 2 cytokines interleukin (IL)-4 and IL-13 in bronchoalveolar lavage fluid and in splenocytes after allergen challenge. The enhanced severity of the asthmatic response from disruption of the Nrf2 pathway was a result of a lowered antioxidant status of the lungs caused by lower basal expression, as well as marked attenuation, of the transcriptional induction of multiple antioxidant genes. Our studies suggest that the responsiveness of Nrf2-directed antioxidant pathways may act as a major determinant of susceptibility to allergen-mediated asthma.
Subfields: Immunology, Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/521e3d0f220448ebedf7ac687e89d306eb34fd70
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Immunology
In Molecular Biology
In Physiology
Citations in the corpus
- An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation (2020, result): “In support of this evidence, several other reports showed enhanced NF-κB activation in Nrf2 knockout mice subdued to different stimuli such as LPS [76], ovalbumin [77], traumatic brain injury [78] and respiratory syncytial virus [79].”
- When NRF2 Talks, Who's Listening? (2010, neutral): “Several experiments have shown increased NF-kB activation in Nrf2 mice when compared with wild-type after stimuli such as traumatic brain injury (65), LPS (147), TNF-a (147), ovalbumin (119), and respiratory syncytial virus (23).”
- ROS Function in Redox Signaling and Oxidative Stress (2014, background): “Antigen-specific adaptive immunity induced by an experimental model of asthma is also intensified by NRF2 deficiency [103].”
- Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. (2006, neutral): “1 mg glutathione S-transferase–IkBa (1-317) substrate (Santa Cruz Biotech-”
- Oxidative stress response and Nrf2 signaling in aging. (2015, neutral): “The Nrf2-associated antioxidant enzymes include the two subunits of glutamate-cysteine ligase (GCL) [48], which catalyze the first and committed step in de novo glutathione (GSH) biosynthesis, all three members of superoxide dismutase [49] family [50, 51], catalase [50], glucose-6-phosphate dehydrog”
- Mechanistic Studies of the Nrf2-Keap1 Signaling Pathway (2006, background): “injury, inflammation, emphysema, asthma, lupus-like autoimmune nephritis, and macular degeneration (Aoki et al., 2001; Yoh et al., 2001; Braun et al., 2002; Cho et al., 2002; Cho et al., 2004; Gao and Talalay, 2004; Suh et al., 2004; Ishii et al., 2005; Rangasamy et al., 2005; Shih et al., 2005a; Sh”
- Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease (2015, neutral): “Inflammatory responses are exacerbated in the absence of Nrf2—In addition to being susceptible to acute chemical toxicity, Nrf2−/− mice are more susceptible to the proinflammatory effects of allergens, lipopolysaccharide, and a high-fat diet [162, 183, 184].”
- NF-kappaB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK. (2008, background): “transgenic mice has proved that Nrf2-ARE pathway is indispensable for body defense against oxidants, carcinogens, and inflammatory insults [14–16].”