UVM Theses and Dissertations
Format:
Print
Author:
Hoffman, Sidra Marie
Dept./Program:
Pathology
Year:
2011
Degree:
MS
Abstract:
Previous work from our laboratory has demonstrated a potential anti-inflammatory effect of the reversible cysteine oxidation, S-glutathionylation (Pantano et al., 2006). The inhibitory effect of S-glutathionylation is overcome by the oxidoreductase, glutaredoxin-1 (Grx1), which catalyses deglutathionylation and enhances NF-kB activation. Although we previously demonstrated that Grx1 expression is increased in mice with allergic inflammation, the impact of Glrx1/S-glutathionylation on allergic inflammation remains unknown. In the present study we sought to examine the imapct of genetic ablation of Glrx1 in the pathogenesis of allergic inflammation and airway hyperresponsiveness in mice.
WT or Glrxr1⁻/⁻ mice in the BALB/c background were subjected to the Alum/Ova model of allergic airways disease, and evaluated 48 hr after 3 challenges, and 48 hr, or 7 days after 6 challenges for various parameters of allergic diseases and the extent of protein-S-glutathionylation. Slight increases in S-glutathionylation were observed in WT mice following sensitization and challenge with Ova, and increases in S-glutathionylation were markedly enhanced in mice lacking Glrx1. Ova-induced inflammation was comparable between WT and Glrxr1⁻/⁻ groups, at alI the timepoints investigated. WT and Glrxr1⁻/⁻ mice demonstrated comparable increases in AHR was still apparent in WT mice, while in contrast, in Glrxr1⁻/⁻ mice all parameters of AHR were resolved to control levels. This was accompanied by a marked decrease in mucus metaplasia compared to controls at this timepoint.
These results demonstrate that the Grx1/S-glutathionylation redox status in mice is a critical regulator of airways hyperresponsiveness, without affecting allergic inflammation. These findings provide new insights into potential mechanisms of AHR, and suggest that avenues to increase S-glutathionylation of specific target proteins may be beneficial to attenuate AHR.
WT or Glrxr1⁻/⁻ mice in the BALB/c background were subjected to the Alum/Ova model of allergic airways disease, and evaluated 48 hr after 3 challenges, and 48 hr, or 7 days after 6 challenges for various parameters of allergic diseases and the extent of protein-S-glutathionylation. Slight increases in S-glutathionylation were observed in WT mice following sensitization and challenge with Ova, and increases in S-glutathionylation were markedly enhanced in mice lacking Glrx1. Ova-induced inflammation was comparable between WT and Glrxr1⁻/⁻ groups, at alI the timepoints investigated. WT and Glrxr1⁻/⁻ mice demonstrated comparable increases in AHR was still apparent in WT mice, while in contrast, in Glrxr1⁻/⁻ mice all parameters of AHR were resolved to control levels. This was accompanied by a marked decrease in mucus metaplasia compared to controls at this timepoint.
These results demonstrate that the Grx1/S-glutathionylation redox status in mice is a critical regulator of airways hyperresponsiveness, without affecting allergic inflammation. These findings provide new insights into potential mechanisms of AHR, and suggest that avenues to increase S-glutathionylation of specific target proteins may be beneficial to attenuate AHR.