Browsing by Subject "Bronchial Hyperreactivity"

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    ItemOpen Access
    Effect of the S-nitrosoglutathione reductase inhibitor N6022 on bronchial hyperreactivity in asthma.
    (Immunity, inflammation and disease, 2018-06) Que, Loretta G; Yang, Zhonghui; Lugogo, Njira L; Katial, Rohit K; Shoemaker, Steven A; Troha, Janice M; Rodman, David M; Tighe, Robert M; Kraft, Monica

    Rationale

    Patients with asthma demonstrate depletion of the endogenous bronchodilator GSNO and upregulation of GSNOR.

    Objectives

    An exploratory proof of concept clinical study of N6022 in mild asthma to determine the potential bronchoprotective effects of GSNOR inhibition. Mechanistic studies aimed to provide translational evidence of effect.

    Methods

    Fourteen mild asthma patients were treated with intravenous N6022 (5 mg) or placebo and observed for 7 days, with repeated assessments of the provocative dose of methacholine causing a 20% fall in FEV1 (methacholine PC20 FEV1), followed by a washout period and crossover treatment and observation. In vitro studies in isolated eosinophils investigated the effect of GSNO and N6022 on apoptosis.

    Measurements and main results

    This was a negative trial as it failed to reach its primary endpoint, which was change from baseline in methacholine PC20 FEV1 at 24 h. However, our exploratory analysis demonstrated significantly more two dose-doubling increases in PC20 FEV1 for N6022 compared with placebo (21% vs 6%, P < 0.05) over the 7-day observation period. Furthermore, a significant treatment effect was observed in the change in PC20 FEV1 from baseline averaged over the 7-day observation period (mean change: +0.82 mg/ml [N6022] from 1.34 mg/ml [baseline] vs -0.18 mg/ml [placebo] from 1.16 mg/ml [baseline], P = 0.023). N6022 was well tolerated in mild asthmatics. In vitro studies demonstrated enhanced eosinophilic apoptosis with N6022.

    Conclusions

    In this early phase exploratory proof of concept trial in asthma, N6022 did not significantly alter methacholine PC20 FEV1 at 24 h, but did have a treatment effect at 7 days compared to baseline. Further investigation of the efficacy of S-nitrosoglutathione reductase inhibition in a patient population with eosinophilic asthma is warranted.
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    ItemOpen Access
    Particulate allergens potentiate allergic asthma in mice through sustained IgE-mediated mast cell activation.
    (2010) Jin, Cong
    In recent years, the incidence of allergic asthma as well as the severity of disease has rapidly increased worldwide. Numerous epidemiological studies have related the exacerbation of allergic asthma with exposure to increased ambient particles from air pollutants. However, the mechanism by which particulate allergens (pAg) exacerbate allergic asthma remains undefined. To evaluate this, we modeled environmental pAg induced allergic asthma by exposing mice to polystyrene beads coated with natural allergen extracts. Compared to equal amounts of soluble allergen extracts (sAg), pAg triggered markedly enhanced airway hyper-responsiveness and pulmonary eosinophilia in allergen sensitized mice. The cellular basis for this effect was determined to be mast cells (MCs), as both airway allergic responses were attenuated in MC deficient KitWsh/KitW-sh mice compared to MC reconstituted KitW-sh/KitW-sh mice. The divergent responses of MCs to pAg versus sAg were due to differences in the termination rate of IgE/FcεRI initiated signaling. Following ligation of sAg, IgE/FcεRI rapidly shuttled into a degradative endosome/lysosome pathway. However, following ligation by pAg, IgE/FcεRI migrated into lipid raft enriched compartments and subsequently failed to follow a degradative pathway, which resulted in a prolonged signaling and heightened synthesis of proinflammatory mediators. These observations highlight the overlooked contributions of the particulate nature of allergens and mast cell endocytic circuitry to the aggravation of allergic asthma.