Browsing by Subject "Forced Expiratory Volume"

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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
    Heritability estimates of endophenotypes of long and health life: the Long Life Family Study.
    (J Gerontol A Biol Sci Med Sci, 2010-12) Matteini, Amy M; Fallin, M Daniele; Kammerer, Candace M; Schupf, Nicole; Yashin, Anatoli I; Christensen, Kaare; Arbeev, Konstantin G; Barr, Graham; Mayeux, Richard; Newman, Anne B; Walston, Jeremy D
    BACKGROUND: Identification of gene variants that contribute to exceptional survival may provide critical biologic information that informs optimal health across the life span. METHODS: As part of phenotype development efforts for the Long Life Family Study, endophenotypes that represent exceptional survival were identified and heritability estimates were calculated. Principal components (PCs) analysis was carried out using 28 physiologic measurements from five trait domains (cardiovascular, cognition, physical function, pulmonary, and metabolic). RESULTS: The five most dominant PCs accounted for 50% of underlying trait variance. The first PC (PC1), which consisted primarily of poor pulmonary and physical function, represented 14.3% of the total variance and had an estimated heritability of 39%. PC2 consisted of measures of good metabolic and cardiovascular function with an estimated heritability of 27%. PC3 was made up of cognitive measures (h(2) = 36%). PC4 and PC5 contained measures of blood pressure and cholesterol, respectively (h(2) = 25% and 16%). CONCLUSIONS: These PCs analysis-derived endophenotypes may be used in genetic association studies to help identify underlying genetic mechanisms that drive exceptional survival in this and other populations.
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    IL-13 in asthma and allergic disease: asthma phenotypes and targeted therapies.
    (The Journal of allergy and clinical immunology, 2012-10) Ingram, Jennifer L; Kraft, Monica
    Decades of research in animal models have provided abundant evidence to show that IL-13 is a key T(H)2 cytokine that directs many of the important features of airway inflammation and remodeling in patients with allergic asthma. Several promising focused therapies for asthma that target the IL-13/IL-4/signal transducer and activator of transcription 6 pathway are in development, including anti-IL-13 mAbs and IL-4 receptor antagonists. The efficacy of these new potential asthma therapies depends on the responsiveness of patients. However, an understanding of how IL-13-directed therapies might benefit asthmatic patients is confounded by the complex heterogeneity of the disease. Recent efforts to classify subphenotypes of asthma have focused on sputum cellular inflammation profiles, as well as cluster analyses of clinical variables and molecular and genetic signatures. Researchers and clinicians can now evaluate biomarkers of T(H)2-driven airway inflammation in asthmatic patients, such as serum IgE levels, sputum eosinophil counts, fraction of exhaled nitric oxide levels, and serum periostin levels, to aid decision making in clinical trials and drug development and to identify subsets of patients who might benefit from therapies. Although it is unlikely that these therapies will benefit all asthmatic patients with this heterogeneous disease, advances in understanding asthma subphenotypes in relation to clinical variables and T(H)2 cytokine responses offer the opportunity to improve the efficacy and safety of proposed therapies for asthma.
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    Impact of lung-function measures on cardiovascular disease events in older adults with metabolic syndrome and diabetes.
    (Clinical cardiology, 2018-07) Lee, Hwa Mu; Zhao, Yanglu; Liu, Michael A; Yanez, David; Carnethon, Mercedes; Graham Barr, R; Wong, Nathan D

    Background

    Individuals with metabolic syndrome (MetS) and diabetes (DM) are more likely to have decreased lung function and are at greater risk of cardiovascular disease (CVD).

    Hypothesis

    Lung-function measures can predict CVD events in older persons with MetS, DM, and neither condition.

    Methods

    We followed 4114 participants age ≥ 65 years with and without MetS or DM in the Cardiovascular Health Study. Cox regression examined the association of forced vital capacity (FVC) and 1-second forced expiratory volume (FEV1 ; percent of predicted values) with incident coronary heart disease and CVD events over 12.9 years.

    Results

    DM was present in 537 (13.1%) and MetS in 1277 (31.0%) participants. Comparing fourth vs first quartiles for FVC, risk of CVD events was 16% (HR: 0.84, 95% CI: 0.59-1.18), 23% (HR: 0.77, 95% CI: 0.60-0.99), and 30% (HR: 0.70, 95% CI: 0.58-0.84) lower in DM, MetS, and neither disease groups, respectively. For FEV1 , CVD risk was lower by 2% (HR: 0.98, 95% CI: 0.70-1.37), 26% (HR: 0.74, 95% CI: 0.59-0.93), and 31% (HR: 0.69, 95% CI: 0.57-0.82) in DM. Findings were strongest for predicting congestive heart failure (CHF) in all disease groups. C-statistics increased significantly with addition of FEV1 or FVC over risk factors for CVD and CHF among those with neither MetS nor DM.

    Conclusions

    FEV1 and FVC are inversely related to CVD in older adults with and without MetS, but not DM (except for CHF); however, their value in incremental risk prediction beyond standard risk factors is limited mainly to metabolically healthier persons.
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    Improved muscle function in a phase I/II clinical trial of albuterol in Pompe disease.
    (Molecular genetics and metabolism, 2020-02) Koeberl, Dwight D; Case, Laura E; Desai, Ankit; Smith, Edward C; Walters, Crista; Han, Sang-Oh; Thurberg, Beth L; Young, Sarah P; Bali, Deeksha; Kishnani, Priya S
    This 24-week, Phase I/II, double-blind, randomized, placebo-controlled study investigated the safety and efficacy of extended-release albuterol in late-onset Pompe disease stably treated with enzyme replacement therapy at the standard dose for 4.9 (1.0-9.4) years and with no contraindications to intake of albuterol. Twelve of 13 participants completed the study. No serious adverse events were related to albuterol, and transient minor drug-related adverse events included muscle spasms and tremors. For the albuterol group, forced vital capacity in the supine position increased by 10% (p < .005), and forced expiratory volume in one second increased by 8% (p < .05); the six-minute walk test increased 25 m (p < .05; excluding one participant unable to complete muscle function testing); the Gross Motor Function Measure increased by 8% (p < .005) with the greatest increases in the Standing (18%; p < .05) and Walking, Running, and Jumping (11%; p < .005) subtests. No significant improvements would be expected in patients with late-onset Pompe disease who were stably treated with enzyme replacement therapy. The placebo group demonstrated no significant increases in performance on any measure. These data support a potential benefit of extended-release albuterol as adjunctive therapy in carefully selected patients with late-onset Pompe disease based on ability to take albuterol on enzyme replacement therapy (NCT01885936).
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    Role of Matrix Metalloproteinases-1 and -2 in Interleukin-13-Suppressed Elastin in Airway Fibroblasts in Asthma.
    (American journal of respiratory cell and molecular biology, 2016-01) Ingram, Jennifer L; Slade, David; Church, Tony D; Francisco, Dave; Heck, Karissa; Sigmon, R Wesley; Ghio, Michael; Murillo, Anays; Firszt, Rafael; Lugogo, Njira L; Que, Loretta; Sunday, Mary E; Kraft, Monica
    Elastin synthesis and degradation in the airway and lung parenchyma contribute to airway mechanics, including airway patency and elastic recoil. IL-13 mediates many features of asthma pathobiology, including airway remodeling, but the effects of IL-13 on elastin architecture in the airway wall are not known. We hypothesized that IL-13 modulates elastin expression in airway fibroblasts from subjects with allergic asthma. Twenty-five subjects with mild asthma (FEV1, 89 ± 3% predicted) and 30 normal control subjects (FEV1, 102 ± 2% predicted) underwent bronchoscopy with endobronchial biopsy. Elastic fibers were visualized in airway biopsy specimens using Weigert's resorcin-fuchsin elastic stain. Airway fibroblasts were exposed to IL-13; a pan-matrix metalloproteinase (MMP) inhibitor (GM6001); specific inhibitors to MMP-1, -2, -3, and -8; and combinations of IL-13 with MMP inhibitors in separate conditions in serum-free media for 48 hours. Elastin (ELN) expression as well as MMP secretion and activity were quantified. Results of this study show that elastic fiber staining of airway biopsy tissue was significantly associated with methacholine PC20 (i.e., the provocative concentration of methacholine resulting in a 20% fall in FEV1 levels) in patients with asthma. IL-13 significantly suppressed ELN expression in asthmatic airway fibroblasts as compared with normal control fibroblasts. The effect of IL-13 on ELN expression was significantly correlated with postbronchodilator FEV1/FVC in patients with asthma. MMP inhibition significantly stimulated ELN expression in patients with asthma as compared with normal control subjects. Specific inhibition of MMP-1 and MMP-2, but not MMP-3 or MMP-8, reversed the IL-13-induced suppression of ELN expression. In asthma, MMP-1 and MMP-2 mediate IL-13-induced suppression of ELN expression in airway fibroblasts.