Oxidants are widely regarded as molecules that contribute to chronic lung inflammation, and a direct role for oxidants in the activation of the transcription factor, Nuclear Factor kappa B, has been suggested. Perhaps surprisingly, during previous funding cycles of this grant, we have demonstrated that S-glutathionylation, a reversible cysteine oxidation, constitutes an active negative feed-back mechanism to shut down NF-?B activation. S-glutathionylation of Inhibitory kappa B kinase beta (IKK?), the most proximal kinase in the canonical NF-?B activation pathway, is critical in inhibiting its catalytic activity. S-glutathionylation of IKK? (IKK?-SSG) occurs in epithelial cells stimulated with lipopolysaccharide (LPS) or house dust mite, and is important in shutting down the activation of NF-?B. IKK?-SSG was reversed by glutaredoxin (Grx1), which under physiological conditions specifically catalyses deglutathionylation, thereby restoring the sulfhydryl group of IKK?, and prolonging NF-?B activation. Mice that systemically lack Grx1 demonstrate accelerated resolution of inflammation and airways hyperresponsiveness (AHR) in response to the antigen, ovalbumin. Conversely, inducible overexpression of Grx1 in bronchiolar epithelium dramatically increases inflammation in response to LPS. These findings point to the importance of the S-glutathionylation/glutaredoxin redox axis as an important module to control the extent and duration of allergic inflammation. Exciting recent findings by our laboratory have illuminated the functional importance of Glutathione S-Transferase pi (GSTP) as a feed forward catalyst of IKK?-SSG that inhibits the activation of NF-?B, and dampens NF-?B driven pro-inflammatory signaling in lung epithelium. GSTP is known classically for its role in phase II drug metabolism. However, a protective role for GSTP in inflammatory lung diseases has emerged, based upon findings of enhanced ovalbumin-induced inflammation and airways hyperresponsiveness in GSTP knock-out mice compared to WT animals, and studies demonstrating a link between a GSTP polymorphism and atopy and bronchial hyperresponsiveness in patients of asthma. However, to date no functional link between GSTP, S-glutathionylation of NF-?B, and expression of pro-inflammatory mediators in epithelial cells has been established. The hypothesis of this proposal is that GSTP and Grx1 act in a balance to control S-glutathionylation of NF-?B. Furthermore, we hypothesize that GSTP-catalyzed S-glutathionylation of the IKK signalsome constitutes an active anti- inflammatory mechanism that dampens allergic airways disease.
In Specific Aim #1 we will determine the functional interrelationship between GSTP and Grx1 in controlling NF-?B activation in lung epithelial cells.
Specific Aim #2 : will address the role of Grx1 and GSTP in airway epithelial cells for the duration of allergic airways disease in mice, and in Specific Aim #3: we seek to unravel the functional determinants of GSTP that govern S-glutathionylation of IKK? and repression of NF-?B. In this aim we will also express human polymorphic variants of GSTP (Ile/Val 105, Ala/Val 114)) and determine their impact of S-glutathionylation of IKK? and regulation of pro-inflammatory signaling. Completion of this application will provide new avenues to limit allergic inflammation, and also provide new insights into the anti-inflammatory mechanism of GSTP, which is essentially unknown.

Public Health Relevance

This project will measure certain chemical events, known as cysteine oxidations in models of asthma. The project will test the hypothesis that increasing these chemical events are important in decreasing inflammation. We will also test certain variants of a human gene, known as glutathione S-transferase P (GSTP) to determine whether these variants differ in their potency to halt inflammation, in order to better understand how gene variations of GSTP relate to asthma. Completion of this project may lead to new strategies to diminish the inflammatory process in patients with asthma.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVRS-G (03))
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Noel, Patricia
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University of Vermont & St Agric College
Schools of Medicine
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Hoffman, Sidra M; Chapman, David G; Lahue, Karolyn G et al. (2016) Protein disulfide isomerase-endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness. J Allergy Clin Immunol 137:822-832.e7
Habibovic, Aida; Hristova, Milena; Heppner, David E et al. (2016) DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma. JCI Insight 1:e88811
Hoffman, Sidra M; Qian, Xi; Nolin, James D et al. (2016) Ablation of Glutaredoxin-1 Modulates House Dust Mite-Induced Allergic Airways Disease in Mice. Am J Respir Cell Mol Biol 55:377-86
Jones, Jane T; Qian, Xi; van der Velden, Jos L J et al. (2016) Glutathione S-transferase pi modulates NF-κB activation and pro-inflammatory responses in lung epithelial cells. Redox Biol 8:375-82
Hristova, Milena; Habibovic, Aida; Veith, Carmen et al. (2016) Airway epithelial dual oxidase 1 mediates allergen-induced IL-33 secretion and activation of type 2 immune responses. J Allergy Clin Immunol 137:1545-1556.e11
Hoffman, Sidra; Nolin, James; McMillan, David et al. (2015) Thiol redox chemistry: role of protein cysteine oxidation and altered redox homeostasis in allergic inflammation and asthma. J Cell Biochem 116:884-92
Anathy, Vikas; Aesif, Scott W; Hoffman, Sidra M et al. (2014) Glutaredoxin-1 attenuates S-glutathionylation of the death receptor fas and decreases resolution of Pseudomonas aeruginosa pneumonia. Am J Respir Crit Care Med 189:463-74
Nolin, James D; Tully, Jane E; Hoffman, Sidra M et al. (2014) The glutaredoxin/S-glutathionylation axis regulates interleukin-17A-induced proinflammatory responses in lung epithelial cells in association with S-glutathionylation of nuclear factor κB family proteins. Free Radic Biol Med 73:143-53
van der Vliet, Albert; Janssen-Heininger, Yvonne M W (2014) Hydrogen peroxide as a damage signal in tissue injury and inflammation: murderer, mediator, or messenger? J Cell Biochem 115:427-35
Hristova, Milena; Veith, Carmen; Habibovic, Aida et al. (2014) Identification of DUOX1-dependent redox signaling through protein S-glutathionylation in airway epithelial cells. Redox Biol 2:436-46

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