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Chitra K Rao,
Charity G Moore,
Eugene Bleecker,
William W Busse,
William Calhoun,
Mario Castro, Kian Fan Chung,
Serpil C Erzurum,
Elliot Israel,
Douglas Curran-Everett,
Sally E Wenzel
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ABSTRACT: Although perimenstrual asthma (PMA) has been associated with severe and difficult-to-control asthma, it remains poorly characterized and understood. The objectives of this study were to identify clinical, demographic, and inflammatory factors associated with PMA and to assess the association of PMA with asthma severity and control.
Women with asthma recruited to the National Heart, Lung, and Blood Institute Severe Asthma Research Program who reported PMA symptoms on a screening questionnaire were analyzed in relation to basic demographics, clinical questionnaire data, immunoinflammatory markers, and physiologic parameters. Univariate comparisons between PMA and non-PMA groups were performed. A severity-adjusted model predicting PMA was created. Additional models addressed the role of PMA in asthma control.
Self-identified PMA was reported in 17% of the subjects (n = 92) and associated with higher BMI, lower FVC % predicted, and higher gastroesophageal reflux disease rates. Fifty-two percent of the PMA group met criteria for severe asthma compared with 30% of the non-PMA group. In multivariable analyses controlling for severity, aspirin sensitivity and lower FVC % predicted were associated with the presence of PMA. Furthermore, after controlling for severity and confounders, PMA remained associated with more asthma symptoms and urgent health-care utilization.
PMA is common in women with severe asthma and associated with poorly controlled disease. Aspirin sensitivity and lower FVC % predicted are associated with PMA after adjusting for multiple factors, suggesting that alterations in prostaglandins may contribute to this phenotype.
Chest 04/2013; 143(4):984-92. · 5.25 Impact Factor
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ABSTRACT: John Widdicombe has made substantial contributions to respiratory physiology and to the field of cough particularly. He was one of the first to characterise Adelta-myelinated fibres in the airways that could mediate cough and increased breathing. Later on, he initiated the series of international London Cough Symposia that gathered researchers and clinicians on a two-yearly basis to discuss recent results and concepts regarding cough. John Widdicombe was interested in all aspects of cough from the definition to potential new antitussives. This article will focus on his contributions and on his generous personality through reminiscences from three friends.
Cough 03/2013; 9(1):6. · 1.26 Impact Factor
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Craig E Wheelock,
Victoria M Goss,
David Balgoma,
Ben Nicholas,
Joost Brandsma,
Paul J Skipp,
Stuart Snowden,
Arnaldo D'Amico,
Ildiko Horvath,
Amphun Chaiboonchoe, [......], Kian Fan Chung,
Paolo Montuschi,
Stephen J Fowler,
Ian M Adcock,
Anthony D Postle,
Sven-Erik Dahlén,
Anthony Rowe,
Peter J Sterk,
Charles Auffray,
Ratko Djukanovic
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ABSTRACT: Inflammatory lung diseases are highly complex in respect of pathogenesis and relationships between inflammation, clinical disease and response to treatment. Sophisticated large-scale analytical methods to quantify gene expression (transcriptomics), proteins (proteomics), lipids (lipidomics) and metabolites (metabolomics) in the lungs, blood and urine are now available to identify biomarkers that define disease in terms of combined clinical, physiological and patho-biological abnormalities. The aspiration is that these approaches will improve diagnosis, i.e., define pathological phenotypes, and facilitate the monitoring of disease and therapy and, also, unravel underlying molecular pathways. Biomarker studies can either select pre-defined biomarker(s) measured by specific methods or apply an "unbiased" approach involving detection platforms that are indiscriminate in focus. This article reviews the technologies presently available to study biomarkers of lung disease within the 'omics field. The contributions of the individual 'omics analytical platforms to the field of respiratory diseases are summarised, with the goal of providing background on their respective abilities to contribute to systems medicine-based studies of lung disease.
European Respiratory Journal 02/2013; · 5.89 Impact Factor
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ABSTRACT: IL-17A induces the release of pro-inflammatory cytokines and of reactive oxygen species which could lead to neutrophilic inflammation. We determined the role of IL-17 receptor (IL-17R) signalling in oxidant-induced lung emphysema and airway hyperresponsiveness. IL-17R(-/-) and wild-type C57/BL6 mice were exposed to ozone (3 ppm; 3 hours) for 12 times over 6 weeks. Bronchial responsiveness to acetylcholine was measured, and lungs were retrieved. Mean linear intercept (Lm) and isometric contractile responses of intrapulmonary airways to acetylcholine were determined. In wild-type mice but not in IL-17R(-/-), chronic ozone exposure caused airway hyperresponsiveness. The increase in Lm after chronic ozone exposure of wild-type mice was also observed in IL-17R(-/-) mice. The increased maximal contractile response to acetylcholine seen in airways of wild-type mice exposed to ozone was abolished in IL-17R(-/-) mice. p38-mitogen-activated protein kinase (MAPK) and dexamethasone-dependent increase in contractile response was reduced in airways from IL-17R(-/-) ozone-exposed mice. Lung inflammation scores were not altered in IL-17R(-/-) mice exposed to ozone compared to wild-type mice. The increased release of IL-17 and IL-1β, and the activation of p38 MAPK in the lungs of ozone-exposed mice was reduced in IL-17R(-/-) mice. IL-17R signalling underlies the increase in airway hyperresponsiveness seen after ozone exposure, mediated by the increased contractility of airway smooth muscle. The emphysema and lung inflammation induced by ozone is not dependent on IL-17.
PLoS ONE 01/2013; 8(3):e58452. · 4.09 Impact Factor
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Fernando Holguin,
Suzy A A Comhair,
Stanley L Hazen,
Robert J Powers,
Sumita S Khatri,
Eugene R Bleecker,
William W Busse,
William J Calhoun,
Mario Castro,
Anne M Fitzpatrick,
Benjamin Gaston,
Elliot Israel,
Nizar N Jarjour,
Wendy C Moore,
Stephen P Peters,
W Gerald Teague, Kian Fan Chung,
Sepill C Erzurum,
Sally E Wenzel
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ABSTRACT: Introduction: Increasing BMI has been associated with less fractional exhaled nitric oxide. This may be explained by an increase in the concentration of asymmetric di-methyl arginine (ADMA) relative to L-arginine, which can lead to greater nitric oxide synthase uncoupling. This mechanism may differ across age of asthma onset and predict asthma morbidity. METHODS: Cross sectional study of participants from the Severe Asthma Research Program (SARP), across early (<12 yrs.) and late (> 12 yrs.) onset asthma phenotypes RESULTS: Late onset asthmatics had a higher median plasma ADMA level (0 .48 μM [IQR 0.35 - 0.7] compared to early onset: (0.37 μM [IQR 0.29 - 0.59], p=0.01), and lower median plasma L-arginine (late onset 52.3 [IQR 43 - 61]) compared to 51 μM [IQR 39 - 66] (early onset); p=0.02). The log of plasma L-arginine/ADMA was inversely correlated with BMI in the late (r = -0.4, p=0.0006) in contrast to the early onset phenotype (r = -0.2, p=0.07). Although FeNO was inversely associated with BMI in the late onset phenotype (p=0.02), the relationship was lost after adjusting for L-arginine/ADMA. Also in this phenotype, a reduced L-arginine/ADMA was associated with less IgE, increased respiratory symptoms, lower lung volumes, and worse asthma quality of life. CONCLUSIONS: In late onset asthma phenotype, plasma ratios of L-arginine to ADMA may explain the inverse relationship of BMI to FeNO. In addition, these lower L-arginine/ADMA ratios are associated with reduced lung function, and increased respiratory symptoms frequency, suggesting a role in the pathobiology of the late onset phenotype.
American Journal of Respiratory and Critical Care Medicine 11/2012; · 11.08 Impact Factor
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The Journal of allergy and clinical immunology 11/2012; · 9.17 Impact Factor
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ABSTRACT: Patients with severe asthma are less responsive to the beneficial effects of corticosteroid therapy.
We investigated whether corticosteroid insensitivity was present in airway smooth muscle cells (ASMCs) of patients with severe asthma.
ASMCs cultured from bronchial biopsy specimens of nonasthmatic control subjects (n = 12) and patients with nonsevere (n = 10) or severe (n = 10) asthma were compared for the effect of dexamethasone on suppression of TNF-α- and IFN-γ-induced CCL11 (eotaxin), CXCL8 (IL-8), and CX3CL1 (fractalkine) expression. The mechanisms of corticosteroid insensitivity are also determined.
CCL11 release was higher in ASMCs of patients with nonsevere but not severe asthma and nonasthmatic control subjects; CXCL8 and CX3CL1 release were similar in all groups. In patients with severe asthma, dexamethasone caused less suppression of CCL11 and CXCL8 release induced by TNF-α. Dexamethasone potentiated TNF-α- and IFN-γ-induced CX3CL1 release equally in all 3 groups. TNF-α-induced phosphorylated p38 mitogen-activated protein kinase levels were increased in ASMCs from patients with severe asthma compared with those from patients with nonsevere asthma and nonasthmatic subjects, whereas TNF-α-induced phosphorylated c-Jun N-terminal kinase and phosphorylated extracellular signal-related kinase levels were increased in all asthmatic groups. A p38 inhibitor increased the inhibitory effect of dexamethasone.
ASMCs of patients with severe asthma are corticosteroid insensitive; this might be secondary to heightened p38 mitogen-activated protein kinase levels.
The Journal of allergy and clinical immunology 09/2012; 130(4):877-885.e5. · 9.17 Impact Factor
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ABSTRACT: Inhaled corticosteroid (ICS) therapy in combination with long-acting β-adrenergic agonists represents the most important treatment
for chronic airways diseases such as asthma and chronic obstructive pulmonary disease (COPD). ICS therapy forms the basis
for treatment of asthma of all severities, improving asthma control, lung function and preventing exacerbations of disease.
Use of ICS has also been established in the treatment of COPD, particularly symptomatic patients, who experience useful gains
in quality of life, likely from an improvement in symptoms such as breathlessness and in reduction in exacerbations, and an
attenuation of the yearly rate of deterioration in lung function. The addition of long-acting β-agonist (LABA) therapy with
ICS increases the efficacy of ICS effects in moderate-to-severe asthma. Thus, a 800μg daily dose of the ICS budesonide reduced
severe exacerbation rates by 49% compared to a low dose of 200μg daily, and addition of the LABA formoterol to budesonide
(800μg) led to a 63% reduction. In COPD, the effects of ICS are less prominent but there are beneficial effects on the decline
in FEV1 and the rate of exacerbations. A reduction in the rate of decline in FEV1 of 16ml/year with a 25% reduction in exacerbation rate has been reported with the salmeterol and fluticasone combination.
A non-significant 17.5% reduction in all-cause mortality rate with ICS and LABA is reported. Chronic inflammation is a feature
of both asthma and COPD, although there are site and characteristic differences. ICS targets this inflammation although this
effect of ICS is less effective in patients with severe asthma and with COPD; however, addition of LABA may potentiate the
anti-inflammatory effects of ICS. An important consideration is the presence of corticosteroid insensitivity in these patients.
Currently available ICS have variably potent binding activities to specific glucocorticoid receptors, leading to inhibition
of gene expression by either binding to DNA and inducing anti-inflammatory genes or by repressing the induction of pro-inflammatory
mediators. Local side effects of ICS include oral candidiasis, hoarseness and dysphonia, while systemic side effects, such
as easy bruising and reduction in growth velocity or bone mineral densitometry, are usually restricted to doses above maximally
recommended doses. Use of LABA alone in patients with asthma increases the risk of asthma-related events including deaths,
but this is less observed with the combination of ICS and LABA. Therefore, use of LABA alone is not recommended for asthma
therapy. Future progress in ICS development will be characterised by the introduction of ICS with greater efficacy with a
limited side-effect profile, and by longer-acting ICS that can be used in combination with once-daily LABAs. Other agents
that could improve the efficacy of corticosteroids or reverse corticosteroid insensitivity may be added to ICS. ICS in combination
with LABAs will continue to remain the main focus of treatment of airways diseases.
European Journal of Clinical Pharmacology 04/2012; 65(9):853-871. · 2.85 Impact Factor
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ABSTRACT: Fibrocytes are circulating progenitor cells that are increased in asthmatic patients with chronic obstructive asthma (COA) and rapid decrease in lung function. Fibrocytes from patients with COA have a greater capacity for proliferation and differentiation.
We investigated whether epidermal growth factor receptor (EGFR) activation mediated the proliferation of fibrocytes in patients with COA and whether oxidative stress was involved in this activation.
Circulating fibrocytes from nonadherent non-T-cell mononuclear cell fractions from healthy subjects, asthmatic patients with normal pulmonary function, and patients with COA were determined by using flow cytometric coexpression of collagen I, CD45, and CD34 or EGFR or a disintegrin and metalloprotease domain 17 and placed in culture.
Expression of EGFR was increased in fibrocytes from patients with COA compared with that seen in patients with NPF. AG1478 and gefitinib, inhibitors of EGFR tyrosine kinase, reduced fibrocyte proliferation and myofibroblast transformation. Increased expression of EGFR and fibrocyte proliferation and transformation were induced by hydrogen peroxide, and these effects were inhibited by N-acetylcysteine.
Enhanced fibrocyte proliferation and transformation found in patients with COA might be mediated through an oxidant-sensitive EGFR-dependent pathway.
The Journal of allergy and clinical immunology 02/2012; 129(5):1367-76. · 9.17 Impact Factor
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ABSTRACT: Severe asthma accounts for a small number of asthmatics but represents a disproportionate cost to health care systems. The underlying mechanism in severe asthma remains unknown but several mechanisms are likely to be involved because of a very heterogeneous profile. We investigated the effects of a p38MAPK inhibitor in corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) from severe asthmatics and the profile of its responders.
Corticosteroid sensitivity was determined by measuring dexamethasone inhibition of CD3/28 and TNF-α induced IL-8 production in PBMCs by using ELISA. PBMCs from severe asthmatics were relatively less sensitive to dexamethasone (Dex) as compared to those of non-severe asthmatics and healthy volunteers. The IC(50) values of Dex negatively correlated with decreased glucocorticoid receptor (GR) nuclear translocation assessed using immunocytochemistry (r = -0.65; p<0.0005) and with decreased FEV(1) (% predicted) (r = 0.6; p<0.0005). A p38α/β inhibitor (SB203580) restored Dex-sensitivity in a subpopulation of severe asthma that was characterized by a defective GR nuclear translocation, clinically by lower FEV(1) and higher use of oral prednisolone. We also found that SB203580 partially inhibited GR phosphorylation at serine 226, resulting in increased GR nuclear translocation in IL-2/IL-4 treated corticosteroid insensitive U937s.
p38MAPKα/β is involved in defective GR nuclear translocation due to phosphorylation at Ser226 and this will be a useful biomarker to identify responders to p38MAPKα/β inhibitor in the future.
PLoS ONE 01/2012; 7(7):e41582. · 4.09 Impact Factor
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Faith S Luyster,
Mihaela Teodorescu,
Eugene Bleecker,
William Busse,
William Calhoun,
Mario Castro, Kian Fan Chung,
Serpil Erzurum,
Elliot Israel,
Patrick J Strollo,
Sally E Wenzel
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ABSTRACT: PURPOSE: The effect of sleep quality on asthma control independent from common comorbidities like gastroesophageal reflux disease (GERD) and obstructive sleep apnea (OSA) is unknown. This study examined the association between sleep quality and asthma control and quality of life after accounting for OSA and GERD in non-severe (NSA) and severe (SA) asthma. METHODS: Cross-sectional data from 60 normal controls, 143 with NSA, and 79 with SA participating in the Severe Asthma Research Program was examined. Those who reported using positive airway pressure therapy or were at high risk for OSA were excluded. RESULTS: Both SA and NSA had poorer sleep quality than controls, with SA reporting the worst sleep quality. All asthmatics with GERD and 92% of those without GERD had poor sleep quality (p = 0.02). The majority (88-100%) of NSA and SA participants who did not report nighttime asthma disturbances still reported having poor sleep quality. In both NSA and SA, poor sleep quality was associated with worse asthma control and quality of life after controlling for GERD and other covariates. CONCLUSIONS: These results suggest that poor sleep quality is associated with poor asthma control and quality of life among asthmatics and cannot be explained by comorbid GERD and nighttime asthma disturbances.
Sleep And Breathing 11/2011; · 1.84 Impact Factor
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Nizar N Jarjour,
Serpil C Erzurum,
Eugene R Bleecker,
William J Calhoun,
Mario Castro,
Suzy A A Comhair, Kian Fan Chung,
Douglas Curran-Everett,
Raed A Dweik,
Sean B Fain, [......],
Eric A Hoffman,
Fernando Holguin,
Bruce D Levy,
Deborah A Meyers,
Wendy C Moore,
Stephen P Peters,
Ronald L Sorkness,
W Gerald Teague,
Sally E Wenzel,
William W Busse
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ABSTRACT: The National Heart, Lung, and Blood Institute Severe Asthma Research Program (SARP) has characterized over the past 10 years 1,644 patients with asthma, including 583 individuals with severe asthma. SARP collaboration has led to a rapid recruitment of subjects and efficient sharing of samples among participating sites to conduct independent mechanistic investigations of severe asthma. Enrolled SARP subjects underwent detailed clinical, physiologic, genomic, and radiological evaluations. In addition, SARP investigators developed safe procedures for bronchoscopy in participants with asthma, including those with severe disease. SARP studies revealed that severe asthma is a heterogeneous disease with varying molecular, biochemical, and cellular inflammatory features and unique structure-function abnormalities. Priorities for future studies include recruitment of a larger number of subjects with severe asthma, including children, to allow further characterization of anatomic, physiologic, biochemical, and genetic factors related to severe disease in a longitudinal assessment to identify factors that modulate the natural history of severe asthma and provide mechanistic rationale for management strategies.
American Journal of Respiratory and Critical Care Medicine 11/2011; 185(4):356-62. · 11.08 Impact Factor
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Eleni Tsitsiou,
Andrew E Williams,
Sterghios A Moschos,
Ketan Patel,
Christos Rossios,
Xiaoying Jiang,
Oona-Delpuech Adams,
Patricia Macedo,
Richard Booton,
David Gibeon, Kian Fan Chung,
Mark A Lindsay
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ABSTRACT: Although previous studies have implicated tissue CD4(+) T cells in the development and maintenance of the inflammatory response in asthmatic patients, little is known about the role of CD8(+) T cells. There is now accumulating evidence that microRNAs and other noncoding RNAs are important regulators of T-cell function.
We sought to use transcriptomics to determine the activation state of circulating CD4(+) and CD8(+) T cells in patients with nonsevere and severe asthma.
mRNA and noncoding RNA expression in circulating T cells was measured by means of microarray, quantitative real-time PCR, or both.
Comparison of mRNA expression showed widespread changes in the circulating CD8(+) but not CD4(+) T cells from patients with severe asthma. No changes were observed in the CD4(+) and CD8(+) T cells in patients with nonsevere asthma versus those in healthy control subjects. Bioinformatics analysis showed that the changes in CD8(+) T-cell mRNA expression were associated with multiple pathways involved in T-cell activation. As with mRNAs, we also observed widespread changes in expression of noncoding RNA species, including natural antisense, pseudogenes, intronic long noncoding RNAs (lncRNAs), and intergenic lncRNAs in CD8(+) T cells from patients with severe asthma. Measurement of the microRNA expression profile showed selective downregulation of miR-28-5p in CD8(+) T cells and reduction of miR-146a and miR-146b in both CD4(+) and CD8(+) T cells.
Severe asthma is associated with the activation of circulating CD8(+) T cells but not CD4(+) T cells. This response is correlated with the downregulation of miR-146a/b and miR-28-5p, as well as changes in the expression of multiple species of lncRNA that might regulate CD8(+) T-cell function.
The Journal of allergy and clinical immunology 09/2011; 129(1):95-103. · 9.17 Impact Factor
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ABSTRACT: With the rapid economic development occurring in the last decade in many countries of Asia, the level of air pollution has increased from both industrial and motor vehicle emissions. Compared with Europe and North America, the potential health effects of this increasing air pollution in Asia remain largely unmeasured. Recent data published by the Health Effects Institute from some major cities in India and China reveal that a 10 µg/m(3) increase in PM(10) was associated with an increase in mortality of 0.6% in daily all-natural cause mortality, with higher risks being found at extremes of high temperatures and in the lowest economically advantaged population. Other Asian studies have confirmed the link between hospital admissions for the worsening of COPD and the increase in asthma prevalence to levels of outdoor air pollutants. Although potential health effects appear to be similar to already-published Western data, it is important that further studies be carried out in Asia that will inform the public and the authorities of the necessity to curb levels of outdoor air pollutants to acceptable levels.
Respirology 08/2011; 16(7):1023-6. · 2.42 Impact Factor
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Dara G Torgerson,
Elizabeth J Ampleford,
Grace Y Chiu,
W James Gauderman,
Christopher R Gignoux,
Penelope E Graves,
Blanca E Himes,
Albert M Levin,
Rasika A Mathias,
Dana B Hancock, [......],
Deborah A Meyers,
Stephanie J London,
Frank D Gilliland,
Esteban G Burchard,
Fernando D Martinez,
Scott T Weiss,
L Keoki Williams,
Kathleen C Barnes,
Carole Ober,
Dan L Nicolae
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ABSTRACT: Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.
Nature Genetics 07/2011; 43(9):887-92. · 35.53 Impact Factor
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ABSTRACT: Aberrant airway smooth muscle cell (ASMC) function and overexpression of transforming growth factor (TGF)-β, which modulates ASMC proliferative and inflammatory function and induces oxidant release, are features of asthma. Nuclear factor E2-related factor 2 (Nrf2) activates antioxidant genes conferring protection against oxidative stress.
To determine the role of Nrf2 in ASMCs and its modulation by TGF-β, and compare Nrf2 activity in ASMCs from subjects with severe and nonsevere asthma and healthy subjects.
ASMCs were cultured from airways of subjects without asthma, and from airway biopsies from patients with severe and nonsevere asthma. We studied Nrf2 activation on antioxidant gene expression and proliferation, the effect of TGF-β on Nrf2 transcriptional activity, and the impact of Nrf2 activation on TGF-β–mediated proliferation and IL-6 release. Nrf2–antioxidant response elements binding and Nrf2-dependent antioxidant gene expression was determined in asthmatic ASMCs.
Activation of Nrf2 led to up-regulation of the antioxidant genes heme oxygenase (HO)-1, NAD(P)H:quinone oxidoreductase, and manganese superoxide dismutase, and a reduction in proliferation. TGF-β reduced Nrf2-mediated antioxidant gene transcription through induction of activating transcription factor-3 expression. Nrf2 activation attenuated TGF-β–mediated reduction in HO-1,ASMC proliferation, and IL-6 release. Nrf2–antioxidant response elements binding was reduced in ASMCs from patients with severe asthma compared with ASMCs from patients with nonsevere asthma and normal subjects. HO-1 expression was reduced in ASMCs from patients with both nonsevere and severe asthma compared with healthy subjects.
Nrf2 regulates antioxidant responses and proliferation in ASMCs and is inactivated by TGF-β. Nrf2 reduction may underlie compromised antioxidant protection and aberrant ASM function in asthma.
American Journal of Respiratory and Critical Care Medicine 07/2011; 184(8):894-903. · 11.08 Impact Factor
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Jean Bousquet,
Josep M Anto,
Peter J Sterk,
Ian M Adcock, Kian Fan Chung,
Josep Roca,
Alvar Agusti,
Chris Brightling,
Anne Cambon-Thomsen,
Alfredo Cesario, [......],
Peter Wellstead,
Olaf Wolkenhauer,
Emiel Wouters,
Rudi Balling,
Anthony J Brookes,
Dominique Charron,
Christophe Pison,
Zhu Chen,
Leroy Hood,
Charles Auffray
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ABSTRACT: We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.
Genome Medicine 07/2011; 3(7):43.
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Kian Fan Chung
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ABSTRACT: The mitogen-activated protein kinase (MAPK) family includes the p38 kinases, which consist of highly conserved proline-directed serine-threonine protein kinases that are activated in response to inflammatory signals. Of the four isoforms, p38α is the most abundant in inflammatory cells and has been the most studied through mainly the availability of small molecule inhibitors. The p38 substrates include transcription factors; other protein kinases, which in turn phosphorylate transcription factors; cytoskeletal proteins and translational components; and other enzymes. Both asthma and COPD are characterized by chronic airflow obstruction, airway and lung remodeling, and chronic inflammation. p38 is involved in the inflammatory responses induced by cigarette smoke exposure, endotoxin, and oxidative stress through activation and release of proinflammatory cytokines/chemokines, posttranslational regulation of these genes, and activation of inflammatory cell migration. Inhibition of p38 MAPK prevented allergen-induced pulmonary eosinophilia, mucus hypersecretion, and airway hyperresponsiveness, effects that may partly result from p38 activation on eosinophil apoptosis and on airway smooth muscle cell production of cytokines/chemokines. In addition, p38 regulates the augmented contractile response induced by oxidative stress. The activation of p38 observed in epithelial cells and macrophages also may underlie corticosteroid insensitivity of severe asthma and COPD. Therefore, p38 inhibitors present a potential attractive treatment of these conditions. Second-generation p38 inhibitors have been disappointing in the treatment of rheumatoid arthritis. In two 6-week studies in patients with COPD, the results were encouraging. Side effects such as liver toxicity remain a possibility, and whether the beneficial effects of p38 inhibitors are clinically significant and sustained need to be determined.
Chest 06/2011; 139(6):1470-9. · 5.25 Impact Factor
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Wendy C Moore,
Michael D Evans,
Eugene R Bleecker,
William W Busse,
William J Calhoun,
Mario Castro, Kian Fan Chung,
Serpil C Erzurum,
Douglas Curran-Everett,
Raed A Dweik,
Benjamin Gaston,
Mark Hew,
Elliot Israel,
Martin L Mayse,
Rodolfo M Pascual,
Stephen P Peters,
Lori Silveira,
Sally E Wenzel,
Nizar N Jarjour
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ABSTRACT: Investigative bronchoscopy was performed in a subset of participants in the Severe Asthma Research Program to gain insights into the pathobiology of severe disease. We evaluated the safety aspects of this procedure in this cohort with specific focus on patients with severe asthma.
To evaluate prospectively changes in lung function and the frequency of adverse events related to investigative bronchoscopy.
Bronchoscopy was performed by using a common manual of procedures. A subset of very severe asthma was defined by severe airflow obstruction, chronic oral corticosteroid use, and recent asthma exacerbations. Subjects were monitored for changes in lung function and contacted by telephone for 3 days after the procedure.
A total of 436 subjects underwent bronchoscopy (97 normal, 196 not severe, 102 severe, and 41 very severe asthma). Nine subjects were evaluated in hospital settings after bronchoscopy; 7 of these were respiratory-related events. Recent emergency department visits, chronic oral corticosteroid use, and a history of pneumonia were more frequent in subjects who had asthma exacerbations after bronchoscopy. The fall in FEV₁ after bronchoscopy was similar in the severe and milder asthma groups. Prebronchodilator FEV₁ was the strongest predictor of change in FEV₁ after bronchoscopy with larger decreases observed in subjects with better lung function.
Bronchoscopy in subjects with severe asthma was well tolerated. Asthma exacerbations were rare, and reduction in pulmonary function after the procedure was similar to that in subjects with less severe asthma. With proper precautions, investigative bronchoscopy can be performed safely in severe asthma.
The Journal of allergy and clinical immunology 04/2011; 128(2):328-336.e3. · 9.17 Impact Factor
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Gaetano Caramori,
Ian M Adcock,
Paolo Casolari,
Kazuhiro Ito,
Elen Jazrawi,
Loukia Tsaprouni,
Gino Villetti,
Maurizio Civelli,
Chiara Carnini, Kian Fan Chung,
Peter J Barnes,
Alberto Papi
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ABSTRACT: Chronic obstructive pulmonary disease (COPD) is characterised by oxidative stress and increased risk of lung carcinoma. Oxidative stress causes DNA damage which can be repaired by DNA-dependent protein kinase complex.
To investigate DNA damage/repair balance and DNA-dependent protein kinase complex in COPD lung and in an animal model of smoking-induced lung damage and to evaluate the effects of oxidative stress on Ku expression and function in human bronchial epithelial cells.
Protein expression was quantified using immunohistochemistry and/or western blotting. DNA damage/repair was measured using colorimetric assays.
8-OH-dG, a marker of oxidant-induced DNA damage, was statistically significantly increased in the peripheral lung of smokers (with and without COPD) compared with non-smokers, while the number of apurinic/apyrimidinic (AP) sites (DNA damage and repair) was increased in smokers compared with non-smokers (p = 0.0012) and patients with COPD (p < 0.0148). Nuclear expression of Ku86, but not of DNA-PKcs, phospho-DNA-PKcs, Ku70 or γ-H2AFX, was reduced in bronchiolar epithelial cells from patients with COPD compared with normal smokers and non-smokers (p < 0.039). Loss of Ku86 expression was also observed in a smoking mouse model (p < 0.012) and prevented by antioxidants. Oxidants reduced (p < 0.0112) Ku86 expression in human bronchial epithelial cells and Ku86 knock down modified AP sites in response to oxidative stress.
Ineffective DNA repair rather than strand breakage per se accounts for the reduced AP sites observed in COPD and this is correlated with a selective decrease of the expression of Ku86 in the bronchiolar epithelium. DNA damage/repair imbalance may contribute to increased risk of lung carcinoma in COPD.
Thorax 04/2011; 66(6):521-7. · 6.84 Impact Factor
