Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages

Goleva, Elena; Hauk, Pia J.; Hall, Clifton F.; Liu, Andrew H.; Riches, David W. H.; Martin, Richard J.; Leung, Donald Y.M.

doi:10.1016/j.jaci.2008.07.007

Cited by 144 publications

(134 citation statements)

References 51 publications

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“…It can be demonstrated in peripheral blood mononuclear cells and alveolar macrophages, and in resident cells such as airway smooth muscle cells from patients with severe asthma [166][167][168][169], but the relationship of these in vitro studies to in vivo responses is not well understood. Corticosteroid insensitivity has been associated with different comorbid conditions such as obesity [170], smoking [171], low vitamin D levels [172,173], and non-eosinophilic (low-Th2 inflammation) mainly in adults [174].…”

Section: Using Established Asthma Medications Corticosteroid Insensitmentioning

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: Using Established Asthma Medications Corticosteroid Insensitmentioning

confidence: 99%

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

et al. 2013

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“…LPS is a major component of the cell walls of Gram-negative bacteria and of allergens that trigger asthma. High levels of LPS have been detected in the bronchoalveolar lavage fluid (BALF) from steroidresistant asthmatics and are an important determinant of the severity of asthma (9,17). We and others have shown that IFN-g-producing cells and LPS contribute to the induction of airway inflammation and AHR in mouse models; furthermore, we have demonstrated that IFN-g/LPS-induced responses are steroid resistant (18,19).…”

mentioning

confidence: 67%

“…Although pulmonary macrophages are known to be critical in host defense against respiratory infection and are activated in the airways of asthmatics (51), their contribution to the disease process and the development of AHR is unclear. Exposure to Ags or increased level of LPS in the airways is associated with the activation of macrophages in asthma (17,48). Interestingly, the levels of CD11b + macrophages in the lung are almost doubled after allergen challenge in patients with asthma (48).…”

Section: Discussionmentioning

confidence: 99%

IL-27/IFN-γ Induce MyD88-Dependent Steroid-Resistant Airway Hyperresponsiveness by Inhibiting Glucocorticoid Signaling in Macrophages

Wang

Baines

et al. 2010

The Journal of Immunology

131

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Inflammation and airway hyperresponsiveness (AHR) are hallmark features of asthma and often correlate with the severity of clinical disease. Although these features of asthma can be effectively managed with glucocorticoid therapy, a subgroup of patients, typically with severe asthma, remains refractory to therapy. The mechanisms leading to steroid resistance in severe asthmatics are poorly understood but may be related to the activation of innate host defense pathways. Previously, we have shown that IFN-γ–producing cells and LPS, two factors that are associated with severe asthma, induce steroid-resistant AHR in a mouse model. We now demonstrate that cooperative signaling induced by IFN-γ and LPS results in the production of IL-27 by mouse pulmonary macrophages. IL-27 and IFN-γ uniquely cooperate to induce glucocorticoid-resistant AHR through a previously unknown MyD88-dependent mechanism in pulmonary macrophages. Importantly, integrated signaling by IL-27/IFN-γ inhibits glucocorticoid-induced translocation of the glucocorticoid receptor to the nucleus of macrophages. Furthermore, expression of both IL-27 and IFN-γ was increased in the induced sputum of steroid-refractory asthmatics. These results suggest that a potential mechanism for steroid resistance in asthma is the activation of MyD88-dependent pathways in macrophages that are triggered by IL-27 and IFN-γ, and that manipulation of these pathways may be a therapeutic target.

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“…Acute exacerbations of asthma, often triggered by respiratory bacterial or viral infections, are critical clinical problems for asthma management and treatment. High levels of LPS and Th1 cytokine IFN-g have been detected in the airways of asthmatics, which are often correlated with asthma severity (3)(4)(5)(6)(7). LPS and IFN-g are two key mediators for exacerbative inflammatory responses and the decrease in sensitivity to steroid in experimental models of asthma (7)(8)(9).…”

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confidence: 99%

Andrographolide Restores Steroid Sensitivity To Block Lipopolysaccharide/IFN-γ–Induced IL-27 and Airway Hyperresponsiveness in Mice

Liao

Tan

Wong

2016

The Journal of Immunology

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LPS and IFN-γ alone or in combination have been implicated in the development of steroid resistance. Combined LPS/IFN-γ strongly upregulates IL-27 production, which has been linked to steroid-resistant airway hyperresponsiveness (AHR). Andrographolide, a bioactive molecule isolated from the plant Andrographis paniculata, has demonstrated anti-inflammatory and antioxidant properties. The present study investigated whether andrographolide could restore steroid sensitivity to block LPS/IFN-γ–induced IL-27 production and AHR via its antioxidative property. The mouse macrophage cell line Raw 264.7, mouse primary lung monocytes/macrophages, and BALB/c mice were treated with LPS/IFN-γ, in the presence and absence of dexamethasone and/or andrographolide. Levels of IL-27 in vitro and in vivo were examined and mouse AHR was assessed. Dexamethasone alone failed to inhibit LPS/IFN-γ–induced IL-27 production and AHR in mice. Andrographolide significantly restored the suppressive effect of dexamethasone on LPS/IFN-γ–induced IL-27 mRNA and protein levels in the macrophage cell line and primary lung monocytes/macrophages, mouse bronchoalveolar lavage fluid and lung tissues, and AHR in mice. LPS/IFN-γ markedly reduced the nuclear level of histone deacetylase (HDAC)2, an essential epigenetic enzyme that mediates steroid anti-inflammatory action. LPS/IFN-γ also decreased total HDAC activity but increased the total histone acetyltransferase/HDAC activity ratio in mouse lungs. Andrographolide significantly restored nuclear HDAC2 protein levels and total HDAC activity, and it diminished the total histone acetyltransferase/HDAC activity ratio in mouse lungs exposed to LPS/IFN-γ, possibly via suppression of PI3K/Akt/HDAC2 phosphorylation, and upregulation of the antioxidant transcription factor NF erythroid-2–related factor 2 level and DNA binding activity. Our data suggest that andrographolide may have therapeutic value in resensitizing steroid action in respiratory disorders such as asthma.

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Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages

Cited by 144 publications

References 51 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

IL-27/IFN-γ Induce MyD88-Dependent Steroid-Resistant Airway Hyperresponsiveness by Inhibiting Glucocorticoid Signaling in Macrophages

Andrographolide Restores Steroid Sensitivity To Block Lipopolysaccharide/IFN-γ–Induced IL-27 and Airway Hyperresponsiveness in Mice

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