Airway inflammation and altered alveolar macrophage phenotype pattern after repeated low‐dose allergen exposure of atopic asthmatic subjects

Lensmar, C.; Prieto, J. Prieto; Dahlén, B.; Eklúnd, Anders; Grünewald, Johan; Roquet, A.

doi:10.1046/j.1365-2222.1999.00757.x

Cited by 42 publications

(55 citation statements)

References 40 publications

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“…CD11b is a component of a-chains of b 2 integrins (52). Higher expression of CD11b reflects the activation of pulmonary macrophages (48,53). Indeed, adoptive transfer of CD11b + pulmonary macrophages induces exaggerated AHR and airway inflammation in a mouse model of asthma (54).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…Indeed, adoptive transfer of CD11b + pulmonary macrophages induces exaggerated AHR and airway inflammation in a mouse model of asthma (54). This suggests that these cells may contribute to the pathogenesis of AHR and inflammation, particularly in relation to recurrent infections (53,55,56).…”

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

View full text Add to dashboard Cite

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“…Moreover, several studies have demonstrated that late asthmatic reaction may occur at doses lower than those inducing early reaction [7]. Indeed, repeated inhalation of low doses, without clinical symptoms, increases bronchial hyperresponsiveness and eosinophil cationic protein levels [19,20]. This continuous exposure without symptoms may also increase the production of antibodies [9].…”

Section: Discussionmentioning

confidence: 99%

“…The current authors have demonstrated that the fall in FEV1 during the specific challenge can be compared to the distribution of the values of FEV1 during the control test with lactose [3]. If the inhaled dose is measured, the specific reactivity can be expressed as the provocative dose of flour causing a 20% or 15% fall in FEV1 (PD f 20 or PD f 15, respectively). Several studies of various allergens have shown that the range of specific reactivity among asthmatic subjects is wide [3,[6][7][8][9].…”

mentioning

confidence: 95%

Bronchial challenge with flour: early response is dependent on the dose of activated allergen inhaled

Choudat

Fabriès²,

Martin³

et al. 2002

Eur Respir J

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Specific bronchial challenges provide information about the relationship between inhaled dose of allergen and change in lung function, but the intermediate pathways remain largely obscure. The aim of this study was to investigate the relationships between the early asthmatic response and 1) the inhaled dose of wheat flour, 2) the concentration of wheat flour, 3) the duration of the exposure, and 4) the deactivation of inhaled allergens and mediators.Thirty-one patients with occupational asthma to wheat flour were studied. Particle aerosols were generated by a computer-controlled aerosoliser and the results were expressed as the provocative dose causing a 20% fall in forced expiratory volume in one second (FEV1) (PD20). The cumulative dose (from the beginning of the challenge), the last inhaled dose, and an estimated dose (taking into account exponential deactivation), were calculated.Twenty patients had high reactivity to flour (reaching a PD20 value). Eleven patients had intermediate reactivity (no measurable PD20 but significantly greater fall in FEV1 compared with lactose challenge). A better correlation between change in FEV1 and dose was obtained for the estimated dose than for the cumulative or last inhaled dose.The bronchial response to wheat flour can be measured by the individual specific hyperreactivity and is expressed by provocative dose of flour. However, deactivation of the allergen and mediators has to be taken into account. This problem can be addressed by using a mathematical model. Eur Respir J 2002; 20: 409-416.

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“…In a diluent controlled evaluation of the challenge, the percentage of eosinophils, interleukin-5 and eosinophil cationic protein in induced sputum were shown to increase [2], and early effects on eosinophils and macrophages in bronchoalveolar lavage fluid have also been reported [9,10]. The aim of the current study was to further characterise the influence of repeated low-dose allergen challenge on the development of airway inflammation.…”

mentioning

confidence: 87%

Early rise in exhaled nitric oxide and mast cell activation in repeated low-dose allergen challenge

Ihre

Gyllfors²,

Gustafsson³

et al. 2006

European Respiratory Journal

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Repeated low-dose allergen inhalation challenge mimics natural allergen exposure, providing a model for early mechanisms in the triggering of asthma. The current authors performed a controlled study to evaluate the time course of changes in exhaled nitric oxide fraction (Fe,NO) and urinary biomarkers of airway inflammation.Eight subjects with mild allergic asthma completed two 7-day repeated low-dose challenge periods, with diluent and allergen, respectively. Subjects were symptom free at inclusion and were investigated when not exposed to specific allergen. Pulmonary function and symptoms were followed, and Fe,NO and urinary mediators were correlated to changes in airway responsiveness to histamine and adenosine.Despite no change in pulmonary function (forced expiratory volume in one second mean¡SEM fall 0.3¡0.7 versus 0.6¡1.0%, for diluent and allergen, respectively) and no asthma symptoms, repeated allergen exposure, in contrast to diluent, caused significant increases in histamine responsiveness (2.3 doubling doses), an early and gradual increase in Fe,NO (up to a doubling from baseline) and a small increase in the mast cell marker 9a11b-prostaglandin F 2 after adenosine challenge.In conclusion, serial measurements of exhaled nitric oxide fraction have the potential to provide a very sensitive strategy for early detection of emerging airway inflammation and subsequent changes in airway hyperresponsiveness to histamine.

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Airway inflammation and altered alveolar macrophage phenotype pattern after repeated low‐dose allergen exposure of atopic asthmatic subjects

Cited by 42 publications

References 40 publications

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

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

Bronchial challenge with flour: early response is dependent on the dose of activated allergen inhaled

Early rise in exhaled nitric oxide and mast cell activation in repeated low-dose allergen challenge

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