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Respiratory Viral Infections and Subversion of Cellular Antioxidant Defenses.

Komaravelli N, Casola A - J Pharmacogenomics Pharmacoproteomics (2014)

Bottom Line: They also reduce antioxidant enzyme (AOE) levels and/or activity, leading to unbalanced oxidative-antioxidant status and subsequent oxidative cell damage.While exposure to several pro-oxidant stimuli usually leads to Nrf2 activation and upregulation of AOE expression, respiratory viral infections are associated with inhibition of AOE expression/activity, which in the case of RSV and hMPV is associated with reduced Nrf2 nuclear localization, decreased cellular levels and reduced ARE-dependent gene transcription.Therefore, administration of antioxidant mimetics or Nrf2 inducers represents potential viable therapeutic approaches to viral-induced diseases, such as respiratory infections and other infections associated with decreased cellular antioxidant capacity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, USA.

ABSTRACT

Reactive oxygen species (ROS) formation is part of normal cellular aerobic metabolism, due to respiration and oxidation of nutrients in order to generate energy. Low levels of ROS are involved in cellular signaling and are well controlled by the cellular antioxidant defense system. Elevated levels of ROS generation due to pollutants, toxins and radiation exposure, as well as infections, are associated with oxidative stress causing cellular damage. Several respiratory viruses, including respiratory syncytial virus (RSV), human metapneumovirus (hMPV) and influenza, induce increased ROS formation, both intracellularly and as a result of increased inflammatory cell recruitment at the site of infection. They also reduce antioxidant enzyme (AOE) levels and/or activity, leading to unbalanced oxidative-antioxidant status and subsequent oxidative cell damage. Expression of several AOE is controlled by the activation of the nuclear transcription factor NF-E2-related factor 2 (Nrf2), through binding to the antioxidant responsive element (ARE) present in the AOE gene promoters. While exposure to several pro-oxidant stimuli usually leads to Nrf2 activation and upregulation of AOE expression, respiratory viral infections are associated with inhibition of AOE expression/activity, which in the case of RSV and hMPV is associated with reduced Nrf2 nuclear localization, decreased cellular levels and reduced ARE-dependent gene transcription. Therefore, administration of antioxidant mimetics or Nrf2 inducers represents potential viable therapeutic approaches to viral-induced diseases, such as respiratory infections and other infections associated with decreased cellular antioxidant capacity.

No MeSH data available.


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Effect of EUK treatment on RSV-induced ROS formation and oxidative stress(A) A549 cells were treated with different micromolar concentrations of EUK-8 and EUK-189, infected with RSV for 24 h, and harvested to measure DCF-DA fluorescence. Ctrl indicates uninfected cells. Mean Fluorescence Intensity is reported as percent increase over control. (B) Cell supernatants were harvested at 24 h p.i. to measure F2-isoprostanes. Results are expressed as mean ± standard error. Results are representative of two independent experiments run in triplicate. *p<0.05, **p<0.01 compared to untreated RSV-infected cells. Reprinted with permission of the American Physiological Society. Copyright © 2014 The American Physiological Society [78].
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Figure 3: Effect of EUK treatment on RSV-induced ROS formation and oxidative stress(A) A549 cells were treated with different micromolar concentrations of EUK-8 and EUK-189, infected with RSV for 24 h, and harvested to measure DCF-DA fluorescence. Ctrl indicates uninfected cells. Mean Fluorescence Intensity is reported as percent increase over control. (B) Cell supernatants were harvested at 24 h p.i. to measure F2-isoprostanes. Results are expressed as mean ± standard error. Results are representative of two independent experiments run in triplicate. *p<0.05, **p<0.01 compared to untreated RSV-infected cells. Reprinted with permission of the American Physiological Society. Copyright © 2014 The American Physiological Society [78].

Mentions: SOD 1 and 2 administration and SOD 3 overexpression have been shown to protect mice lungs from influenza-induced oxidative stress damage [72]. Both SOD 1 and 2 administration, either parenterally or intranasal in a cotton rat model of RSV infection, reduced pulmonary viral titer [73]. In the past few years, quite a few classes of synthetic SOD mimetics that are based on organo-manganese complexes have been developed and explored as possible therapeutics against oxidant-related lung damage [74]. In a recent study, the effect of airway epithelial cell treatment with various Eukarionsalen-manganese complexes (EUK) on cellular signaling and oxidative stress in response to RSV infection was assessed. EUKs are synthetic salen-manganese complexes that exhibit SOD and catalase activities [75]. Salen complexes are Schiff bases, usually prepared by the condensation of a salicylaldehyde with an amine. Based on the salen ring substitutes, EUKs are named from EUK-8 to EUK-189 and have different rates of SOD and catalase/peroxidase activities [76,77]. Treatment of RSV-infected airway epithelial cells with EUK-8, -134 and -189, which have SOD and catalase/peroxidase activity, results in significantly reduced ROS levels (Figure 3A) and markers of oxidative cell damage (Figure 3B). In addition, EUK treatment is associated with reduced activation of the viral-induced transcription factors NF-κB and IRF-3 and reduced secretion of cytokines and chemokines [8,78]. Enhancement of both SOD and catalase/GPx activities is important to reduce ROS levels and pro-inflammatory gene expression during RSV infection, as EUK-163, which has no significant catalase or peroxidase activity, does not have a significant effect on RSV-induced pro-inflammatory mediator secretion [8]. In addition, EUK treatment in high concentration (500 μM) significantly reduce viral replication [78], suggesting that EUKs could represent a novel therapeutic approach to modulate RSV-induced lung damage.


Respiratory Viral Infections and Subversion of Cellular Antioxidant Defenses.

Komaravelli N, Casola A - J Pharmacogenomics Pharmacoproteomics (2014)

Effect of EUK treatment on RSV-induced ROS formation and oxidative stress(A) A549 cells were treated with different micromolar concentrations of EUK-8 and EUK-189, infected with RSV for 24 h, and harvested to measure DCF-DA fluorescence. Ctrl indicates uninfected cells. Mean Fluorescence Intensity is reported as percent increase over control. (B) Cell supernatants were harvested at 24 h p.i. to measure F2-isoprostanes. Results are expressed as mean ± standard error. Results are representative of two independent experiments run in triplicate. *p<0.05, **p<0.01 compared to untreated RSV-infected cells. Reprinted with permission of the American Physiological Society. Copyright © 2014 The American Physiological Society [78].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4288774&req=5

Figure 3: Effect of EUK treatment on RSV-induced ROS formation and oxidative stress(A) A549 cells were treated with different micromolar concentrations of EUK-8 and EUK-189, infected with RSV for 24 h, and harvested to measure DCF-DA fluorescence. Ctrl indicates uninfected cells. Mean Fluorescence Intensity is reported as percent increase over control. (B) Cell supernatants were harvested at 24 h p.i. to measure F2-isoprostanes. Results are expressed as mean ± standard error. Results are representative of two independent experiments run in triplicate. *p<0.05, **p<0.01 compared to untreated RSV-infected cells. Reprinted with permission of the American Physiological Society. Copyright © 2014 The American Physiological Society [78].
Mentions: SOD 1 and 2 administration and SOD 3 overexpression have been shown to protect mice lungs from influenza-induced oxidative stress damage [72]. Both SOD 1 and 2 administration, either parenterally or intranasal in a cotton rat model of RSV infection, reduced pulmonary viral titer [73]. In the past few years, quite a few classes of synthetic SOD mimetics that are based on organo-manganese complexes have been developed and explored as possible therapeutics against oxidant-related lung damage [74]. In a recent study, the effect of airway epithelial cell treatment with various Eukarionsalen-manganese complexes (EUK) on cellular signaling and oxidative stress in response to RSV infection was assessed. EUKs are synthetic salen-manganese complexes that exhibit SOD and catalase activities [75]. Salen complexes are Schiff bases, usually prepared by the condensation of a salicylaldehyde with an amine. Based on the salen ring substitutes, EUKs are named from EUK-8 to EUK-189 and have different rates of SOD and catalase/peroxidase activities [76,77]. Treatment of RSV-infected airway epithelial cells with EUK-8, -134 and -189, which have SOD and catalase/peroxidase activity, results in significantly reduced ROS levels (Figure 3A) and markers of oxidative cell damage (Figure 3B). In addition, EUK treatment is associated with reduced activation of the viral-induced transcription factors NF-κB and IRF-3 and reduced secretion of cytokines and chemokines [8,78]. Enhancement of both SOD and catalase/GPx activities is important to reduce ROS levels and pro-inflammatory gene expression during RSV infection, as EUK-163, which has no significant catalase or peroxidase activity, does not have a significant effect on RSV-induced pro-inflammatory mediator secretion [8]. In addition, EUK treatment in high concentration (500 μM) significantly reduce viral replication [78], suggesting that EUKs could represent a novel therapeutic approach to modulate RSV-induced lung damage.

Bottom Line: They also reduce antioxidant enzyme (AOE) levels and/or activity, leading to unbalanced oxidative-antioxidant status and subsequent oxidative cell damage.While exposure to several pro-oxidant stimuli usually leads to Nrf2 activation and upregulation of AOE expression, respiratory viral infections are associated with inhibition of AOE expression/activity, which in the case of RSV and hMPV is associated with reduced Nrf2 nuclear localization, decreased cellular levels and reduced ARE-dependent gene transcription.Therefore, administration of antioxidant mimetics or Nrf2 inducers represents potential viable therapeutic approaches to viral-induced diseases, such as respiratory infections and other infections associated with decreased cellular antioxidant capacity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, USA.

ABSTRACT

Reactive oxygen species (ROS) formation is part of normal cellular aerobic metabolism, due to respiration and oxidation of nutrients in order to generate energy. Low levels of ROS are involved in cellular signaling and are well controlled by the cellular antioxidant defense system. Elevated levels of ROS generation due to pollutants, toxins and radiation exposure, as well as infections, are associated with oxidative stress causing cellular damage. Several respiratory viruses, including respiratory syncytial virus (RSV), human metapneumovirus (hMPV) and influenza, induce increased ROS formation, both intracellularly and as a result of increased inflammatory cell recruitment at the site of infection. They also reduce antioxidant enzyme (AOE) levels and/or activity, leading to unbalanced oxidative-antioxidant status and subsequent oxidative cell damage. Expression of several AOE is controlled by the activation of the nuclear transcription factor NF-E2-related factor 2 (Nrf2), through binding to the antioxidant responsive element (ARE) present in the AOE gene promoters. While exposure to several pro-oxidant stimuli usually leads to Nrf2 activation and upregulation of AOE expression, respiratory viral infections are associated with inhibition of AOE expression/activity, which in the case of RSV and hMPV is associated with reduced Nrf2 nuclear localization, decreased cellular levels and reduced ARE-dependent gene transcription. Therefore, administration of antioxidant mimetics or Nrf2 inducers represents potential viable therapeutic approaches to viral-induced diseases, such as respiratory infections and other infections associated with decreased cellular antioxidant capacity.

No MeSH data available.


Related in: MedlinePlus