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Oxidative Lung Injury in Virus-Induced Wheezing

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Technical Report,01 May 2010,30 Apr 2015

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The University of Texas Medical Branch at Galveston Galveston United States

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We have focused on the role of the transcription factor Nrf2 in controlling expression of antioxidant enzymes AOE genes in the lung following infection by respiratory viruses, in particular respiratory syncytial virus RSV. We have shown that an NRF2-inducing agent, BHA, can restore in part expression of the antioxidant genes SOD1 and catalase following RSV infection in mice. We have also shown that EUKs antioxidant mimetics modulate oxidative stress and inflammatory response in human epithelial cells infected by RSV. Our data show that RSV infection induces NRF2 deacetylation, ubiquitination, and degradation via the proteasome pathway both in vitro and in vivo. Histone deacetylase HDAC and proteasome inhibitors block NRF2degradation and increase NRF2 binding to endogenous promoter ARE sites, resulting in increased AOE expression. Known inducers of NRF2 are able to increase NRF2 activation and subsequent AOE expression during RSV infection in AECs, as well as in an animal model of infection, with significant amelioration of oxidative stress, which is an important pathogenic component of virus-induced lung disease, adding additional support to the concept that therapeutic strategies aimed to increase airway antioxidant capacity by increasing NRF2 activity could be beneficial in RSV infection. Recently, using an in vitro model of RSV infection of airway epithelial cells, we discovered that RSV infection inhibits the expression of the CSE enzyme and reduces the ability to generate cellular hydrogen sulfide H2S, an endogenous gasotransmitter that we have identified as a novel antiviral pathway. We have presented these data at several national and international meetings and published our findings in high impact factor scientific journals.

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