Increased phenotypic differentiation and reduced corticosteroid sensitivity of fibrocytes in severe asthma

Lo, Ching-Jung; Michaeloudes, Charalambos; Bhavsar, Pankaj; Huang, Chiung‐Yi; Wang, Chun Hua; Kuo, Han Pin; Chung, Kian Fan

doi:10.1016/j.jaci.2014.10.031

Cited by 37 publications

(39 citation statements)

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“…An absence of effect might be related to recent in vitro observations by Lo et al, 32 who reported the absence of dexamethasone-induced apoptosis on cultured fibrocytes from peripheral blood of patients with severe asthma, which contrasted with the steroid-induced apoptotic effect on fibrocytes cultured from patients with nonsevere asthma and control subjects.…”

Section: Discussionmentioning

confidence: 84%

Number, activation, and differentiation of circulating fibrocytes correlate with asthma severity

Shipe

Burdick

Strieter

et al. 2016

Journal of Allergy and Clinical Immunology

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Background A biomarker that predicts poor asthma control would be clinically useful. Fibrocytes are bone marrow–derived circulating progenitor cells that have been implicated in tissue fibrosis and TH2 responses in asthmatic patients. Objective We sought to test the hypothesis that the concentration and activation state of peripheral blood fibrocytes correlates with asthma severity. Methods By using fluorescence-activated cell sorting analysis, fibrocytes (CD45+ and collagen 1 [Col1]+) were enumerated and characterized in the buffy coats of fresh peripheral blood samples from 15 control subjects and 40 asthmatic patients. Results Concentrations of peripheral blood total (CD45+Col1+), activated (the TGF-β transducing protein phosphorylated SMAD2/3 [p-SMAD2/3]+ or phosphorylated AKT [p-AKT]+), and differentiated (α-smooth muscle actin [α-SMA]+) fibrocytes were increased in asthmatic patients compared with control subjects. The increase in total and CD45+Col1+CXCR4+ fibrocytes was primarily seen in patients with severe asthma (Global Initiative for Asthma steps 4–5) as opposed to those with milder asthma (Global Initiative for Asthma steps 1–3). In addition, numbers of circulating α-SMA+ and α-SMA+CXCR4+ fibrocytes were increased in asthmatic patients experiencing an asthma exacerbation in the preceding 12 months. A significant correlation (P <.05) was observed between CD45+Col1+CXCR4+ fibrocytes and the activation phenotypes CD45+Col1+p-SMAD2/3+ and CD45+Col1+p-AKT+. Conclusion There was correlation between circulating fibrocyte subsets and asthma severity, and there was an increased number of activated/differentiated fibrocytes in circulating blood of asthmatic patients experiencing an exacerbation in the preceding 12 months.

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Section: Discussionmentioning

confidence: 84%

Number, activation, and differentiation of circulating fibrocytes correlate with asthma severity

Shipe

Burdick

Strieter

et al. 2016

Journal of Allergy and Clinical Immunology

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“…It is possible that Th2-low patients will require therapies that are specifically targeted to structural changes rather than inflammation, but this has yet to be shown. However, in support of this hypothesis, adults with severe steroid-resistant asthma have increased circulating fibrocytes ( progenitors of mesenchymal cells that are less responsive to steroids) compared with patients with milder disease [30].…”

Section: Limitations Of Therapy Targeted At Inflammationmentioning

confidence: 99%

Novel concepts in airway inflammation and remodelling in asthma

2015

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The hallmark pathological features of asthma include airway eosinophilic inflammation and structural changes (remodelling) which are associated with an irreversible loss in lung function that tracks from childhood to adulthood. In parallel with changes in function, pathological abnormalities occur early, during the pre-school years, are established by school age and subsequently remain (even though symptoms may remit for periods during adulthood). Given the equal importance of inflammation and remodelling in asthma pathogenesis, there is a significant disparity in studies undertaken to investigate the contribution of each. The majority focus on the role of inflammation, and although novel therapeutics such as those targeted against T-helper cell type 2 (Th2) mediators have arisen, it is apparent that targeting inflammation alone has not allowed disease modification. Therefore, unless airway remodelling is addressed for future therapeutic strategies, it is unlikely that we will progress towards a cure for asthma. Having acknowledged these limitations, the focus of this review is to highlight the gaps in our current knowledge about the mechanisms underlying airway remodelling, the relationships between remodelling, inflammation and function, remodelling and clinical phenotypes, and the importance of utilising innovative and realistic pre-clinical models to uncover effective, disease-modifying therapeutic strategies. @ERSpublications We discuss mechanisms of airway inflammation and remodelling in asthma to uncover effective therapeutic strategies http://ow.ly/SsXiO

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“…Thus, the definition of “severe” asthma is applied to patients whose symptoms or exacerbations require the use of a high-dose inhaled corticosteroid plus a second controller, or whose disease persists in spite of treatment [56, 57]. The understanding of asthma physiopathology has allowed the design of treatments for these persistent cases based on anti-IgE monoclonal antibodies such as OmAb.…”

Section: Anti-ige-based Treatmentsmentioning

confidence: 99%

IgE-Related Chronic Diseases and Anti-IgE-Based Treatments

Navinés-Ferrer

Serrano‐Candelas

Molina-Molina

et al. 2016

Journal of Immunology Research

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IgE is an immunoglobulin that plays a central role in acute allergic reactions and chronic inflammatory allergic diseases. The development of a drug able to neutralize this antibody represents a breakthrough in the treatment of inflammatory pathologies with a probable allergic basis. This review focuses on IgE-related chronic diseases, such as allergic asthma and chronic urticaria (CU), and on the role of the anti-IgE monoclonal antibody, omalizumab, in their treatment. We also assess the off-label use of omalizumab for other pathologies associated with IgE and report the latest findings concerning this drug and other new related drugs. To date, omalizumab has only been approved for severe allergic asthma and unresponsive chronic urticaria treatments. In allergic asthma, omalizumab has demonstrated its efficacy in reducing the dose of inhaled corticosteroids required by patients, decreasing the number of asthma exacerbations, and limiting the effect on airway remodeling. In CU, omalizumab treatment rapidly improves symptoms and in some cases achieves complete disease remission. In systemic mastocytosis, omalizumab also improves symptoms and its prophylactic use to prevent anaphylactic reactions has also been discussed. In other pathologies such as atopic dermatitis, food allergy, allergic rhinitis, nasal polyposis, and keratoconjunctivitis, omalizumab significantly improves clinical manifestations. Omalizumab acts in two ways: by sequestering free IgE and by accelerating the dissociation of the IgE-Fcε receptor I complex.

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Increased phenotypic differentiation and reduced corticosteroid sensitivity of fibrocytes in severe asthma

Abstract: Patients with severe asthma have elevated numbers of circulating fibrocytes that show enhanced myofibroblastic differentiation and that are less responsive to the effects of corticosteroids.

Cited by 37 publications

References 38 publications

Number, activation, and differentiation of circulating fibrocytes correlate with asthma severity

Number, activation, and differentiation of circulating fibrocytes correlate with asthma severity

Novel concepts in airway inflammation and remodelling in asthma

IgE-Related Chronic Diseases and Anti-IgE-Based Treatments

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