Airway remodeling in subjects with severe asthma with or without chronic persistent airflow obstruction

Kamińska, Marta; Foley, Susan; Maghni, Karim; Storness-Bliss, Claudine; Coxson, Harvey O.; Ghezzo, Heberto; Lemière, Catherine; Olivenstein, Ronald; Ernst, Pierre; Hamid, Qutayba; Martin, James G.

doi:10.1016/j.jaci.2009.03.049

Cited by 195 publications

(173 citation statements)

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“…First, the epithelium in severe asthma is reported to be thicker than in mild-to-moderate asthma [104], with altered proliferation, apoptosis and release of proinflammatory factors [105]. Second, autopsy and biopsy studies have linked an increased amount of airway smooth muscle to asthma severity, airflow obstruction and bronchial hyperresponsiveness [71,[106][107][108][109]. Finally, fibrocytes, which can differentiate into myofibroblasts, are increased in blood and in smooth muscle bundles in asthmatics with fixed airways obstruction and/or severe asthma [110,111].…”

Section: Structural Abnormalitiesmentioning

confidence: 99%

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

et al. 2013

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Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults.A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations.When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided.Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

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Section: Structural Abnormalitiesmentioning

confidence: 99%

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

et al. 2013

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“…In particular, MC-derived IL-17 may contribute to the progress of inflammation, inducing epithelial cells to promote neutrophil accumulation into the site of injury. Moreover, IL-6 and IL-13 production are also associated with a pattern of airway remodeling (45), contributing to the overall worsening of the disease. Our study highlights a new and previously unappreciated role of MCs through AhR activation in orchestrating inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

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Calvaruso

et al. 2012

The Journal of Immunology

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The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor whose activity is modulated by xenobiotics as well as physiological ligands. These compounds may modulate inflammatory responses and contribute to the rising prevalence of allergic diseases observed in industrialized countries. Mast cells (MCs), located within tissues at the boundary of the external environment, represent a potential target of AhR ligands. In this study, we report that murine and human MCs constitutively express AhR, and its activation by the high-affinity ligand 6-formylindolo[3,2-b]carbazole (FICZ) determines a boost in degranulation. On the contrary, repeated exposure to FICZ inhibits MC degranulation. Accordingly, histamine release, in an in vivo passive systemic anaphylactic model, is exacerbated by a single dose and is attenuated by repetitive stimulation of AhR. FICZ-exposed MCs produce reactive oxygen species and IL-6 in response to cAMP-dependent signals. Moreover, AhR-activated MCs produce IL-17, a critical player in chronic inflammation and autoimmunity, suggesting a novel pathway for MC activation in the pathogenesis of these diseases. Indeed, histological analysis of patients with chronic obstructive pulmonary disease revealed an enrichment in AhR/IL-6 and AhR/IL-17 double-positive MCs within bronchial lamina propria. Thus, tissue-resident MCs could translate external chemical challenges through AhR by modulating allergic responses and contributing to the generation of inflammation-related diseases.

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“…However, these analyses showed no significant difference between ETN and placebo for FEV1 reversibility by tertile subgroup (f16%, .16% and f24%, and .24% improvement from pre-bronchodilator FEV1 % pred at baseline). Severe corticosteroid refractory asthma is characterised by reduced bronchodilator reversibility, possibly as a consequence of airway wall remodelling [33,34]. It remains possible that selection of patients on the basis of greater bronchodilator response and/or bronchial hyperresponsiveness might have revealed some efficacy.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial

et al. 2010

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Increased tumour necrosis factor-a levels have been observed in bronchial biopsies and induced sputum from subjects with severe asthma. We investigated etanercept (ETN) as a therapeutic option for treating moderate-to-severe persistent asthma.In this 12-week, randomised, double-blind, placebo-controlled, phase 2 trial, subjects (n5132) with moderate-to-severe persistent asthma received subcutaneous injections of 25 mg ETN or placebo twice weekly, and were evaluated at baseline, and at weeks 2, 4, 8 and 12. The primary end-point was the change from baseline to week 12 in pre-bronchodilator forced expiratory volume in 1 s (FEV1) % predicted. Secondary end-points included morning peak expiratory flow, FEV1 % pred, Asthma Control Questionnaire (5-item version), asthma exacerbations, provocative concentration of methacholine causing a 20% decrease in FEV1, and the Asthma Quality of Life Questionnaire.No significant differences were observed between ETN and placebo for any of the efficacy endpoints. ETN treatment was well tolerated, with no unexpected safety findings observed during the study.Clinical efficacy of ETN was not shown in subjects with moderate-to-severe persistent asthma over 12 weeks. However, ETN treatment was a well-tolerated therapy. Studies in specific subsets of patients with asthma with longer-term follow-up may be needed to fully evaluate the clinical efficacy of ETN in this population.

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Airway remodeling in subjects with severe asthma with or without chronic persistent airflow obstruction

Cited by 195 publications

References 50 publications

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

The Aryl Hydrocarbon Receptor Modulates Acute and Late Mast Cell Responses

Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial

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