Antioxidant Strategies in the Treatment of Bronchial Asthma

Joyce-Brady, Martin; Cruikshank, William W.; Doctrow, Susan R.

doi:10.5772/29250

Cited by 1 publication

(2 citation statements)

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“…This permits one to focus on lung airway epithelial cells and their response to the inflammatory process (Joyce-Brady et al, 2012). Similarity of the inflammatory response after IL-13 delivery to the lung in this study is suggested by the comparable levels of induction of IL33 cytokine messenger RNA and eosinophilic infiltrate in bronchoalveolar lavage fluid compared to untreated controls in the absence or presence of GGsTop.…”

Section: Discussionmentioning

confidence: 99%

“…IL-13 is a well described pro-inflammatory cytokine that drives inflammation in a mouse model of experimental asthma (Grunig et al, 1998; Zhu et al, 1999). This cytokine-driven model evokes a similar degree of inflammatory cell infiltration into the lungs of normal mice and GGT enu1 mutant mice, thereby allowing study of their lung response to inflammation (Lowry et al, 2008; Joyce-Brady et al, 2012). We found that the GGT deficient GGT enu1 mouse was protected against asthma in this model by an increased size of the extracellular LLF glutathione pool which buffered oxidant species derived from inflammatory cells, and preserved airway epithelial cell barrier function.…”

Section: Introductionmentioning

confidence: 99%

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Inhibiting lung lining fluid glutathione metabolism with GGsTop as a novel treatment for asthma

et al. 2014

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Asthma is characterized by airway inflammation. Inflammation is associated with oxidant stress. Airway epithelial cells are shielded from this stress by a thin layer of lung lining fluid (LLF) which contains an abundance of the antioxidant glutathione. LLF glutathione metabolism is regulated by γ-glutamyl transferase (GGT). Loss of LLF GGT activity in the mutant GGTenu1 mouse causes an increase in baseline LLF glutathione content which is magnified in an IL-13 model of allergic airway inflammation and protective against asthma. Normal mice are susceptible to asthma in this model but can be protected with acivicin, a GGT inhibitor. GGT is a target to treat asthma but acivicin toxicity limits clinical use. GGsTop is a novel GGT inhibitor. GGsTop inhibits LLF GGT activity only when delivered through the airway. In the IL-13 model, mice treated with IL-13 and GGsTop exhibit a lung inflammatory response similar to that of mice treated with IL-13 alone. But mice treated with IL-13 and GGsTop show attenuation of methacholine-stimulated airway hyper-reactivity, inhibition of Muc5ac and Muc5b gene induction, decreased airway epithelial cell mucous accumulation and a fourfold increase in LLF glutathione content compared to mice treated with IL-13 alone. Mice treated with GGsTop alone are no different from that of mice treated with saline alone, and show no signs of toxicity. GGsTop could represent a valuable pharmacological tool to inhibit LLF GGT activity in pulmonary disease models. The associated increase in LLF glutathione can protect lung airway epithelial cells against oxidant injury associated with inflammation in asthma.

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Section: Discussionmentioning

confidence: 99%