气道高反应性反映哮喘表型中皮质类固醇敏感肥大细胞的参与
2023/04/21
摘要
背景：气道高反应性是哮喘表型的标志。气道对甘露醇的高反应性与气道肥大细胞浸润有关，这表明尽管2型炎症水平较低，吸入皮质类固醇可以有效降低对甘露醇的反应。
目的：RECONSTRUCT研究的目的是研究气道高反应性和浸润性肥大细胞之间的关系，以及吸入皮质类固醇治疗的反应。
方法：在50例对甘露醇有气道高反应性的无皮质类固醇患者中，每天1600μg布地奈德治疗6周前后进行粘膜冷冻活检。根据基线FeNO对患者进行分层，截止值为25ppb。
结果：FeNO高和FeNO低哮喘的气道高反应性在基线时具有可比性，并在治疗后得到同等改善：加倍剂量：分别为3.98（95%CI:2.49-6.38，P<0.001）和3.85（95%CI:2.51-5.91，<0.001）。然而，两组肥大细胞的表型和分布不同：在FeNO高哮喘中，气道高反应性与浸润上皮层的糜蛋白酶高肥大细胞密度相关（ρ：-0.42 P=0.04），在FeNO低哮喘中，吸入皮质类固醇后气道高反应性的改善与肥大细胞以及气道TSLP和IL33的减少有关。
结论：气道对甘露醇的高反应性与哮喘表型中的肥大细胞浸润有关，与FeNO高哮喘的上皮肥大细胞和FeNO低哮喘的气道平滑肌肥大细胞有关。在两组患者中，吸入皮质类固醇治疗均能有效降低气道高反应性。
Airway Hyperresponsiveness Reflects Corticosteroid-Sensitive Mast Cell Involvement Across Asthma Phenotypes
Morten Hvidtfeldt, Asger Sverrild, Alexis Pulga, Laurits Frøssing, Alexander Silberbrandt, Morten Hostrup, Martin Thomassen, Caroline Sanden, Carl Magnus Clausson, Premkumar Siddhuraj, Daisy Bornesund, Juan Jose Nieto-Fontarigo, Lena Uller, Jonas Erjefält, Celeste Porsbjerg
Abstract
Background: Airway hyperresponsiveness is a hallmark of asthma across asthma phenotypes. Airway hyperresponsiveness to mannitol specifically relates to mast cell infiltration of the airways, suggesting inhaled corticosteroids to be effective in reducing the response to mannitol, despite low levels of type 2 inflammation.
Objective: The aim of the RECONSTRUCT study was to investigate the relationship between airway hyperresponsiveness and infiltrating mast cells, and the response to inhaled corticosteroid treatment.
Methods: In 50 corticosteroid-free patients with airway hyperresponsiveness to mannitol, mucosal cryobiopsies were obtained before and after 6 weeks daily treatment with 1600μg budesonide. Patients were stratified according to baseline FeNO with a cut-off of 25ppb.
Results: Airway hyperresponsiveness was comparable at baseline and improved equally with treatment in both FeNO-high and FeNO-low asthma: doubling dose: 3.98 (95% CI:2.49-6.38, P<0.001) and 3.85 (95% CI: 2.51-5.91, P<0.001), respectively. However, phenotypes and distribution of mast cells differed between the two groups: In FeNO-high asthma, Airway hyperresponsiveness correlated to the density of chymase high mast cells infiltrating the epithelial layer (ρ: -0.42 P= 0.04), and in FeNO-low asthma, to the density in airway smooth muscle (ρ: -0.51, P=0.02). The improvement in airway hyperresponsiveness after inhaled corticosteroids correlated with a reduction in mast cells, as well as in airway TSLP and IL33.
Conclusions: Airway hyperresponsiveness to mannitol is related to mast cell infiltration across asthma phenotypes, correlating with epithelial mast cells in FeNO-high asthma, and airway smooth muscle mast cells in FeNO-low asthma. Treatment with inhaled corticosteroids was effective in reducing airway hyperresponsiveness in both groups.
背景：气道高反应性是哮喘表型的标志。气道对甘露醇的高反应性与气道肥大细胞浸润有关，这表明尽管2型炎症水平较低，吸入皮质类固醇可以有效降低对甘露醇的反应。
目的：RECONSTRUCT研究的目的是研究气道高反应性和浸润性肥大细胞之间的关系，以及吸入皮质类固醇治疗的反应。
方法：在50例对甘露醇有气道高反应性的无皮质类固醇患者中，每天1600μg布地奈德治疗6周前后进行粘膜冷冻活检。根据基线FeNO对患者进行分层，截止值为25ppb。
结果：FeNO高和FeNO低哮喘的气道高反应性在基线时具有可比性，并在治疗后得到同等改善：加倍剂量：分别为3.98（95%CI:2.49-6.38，P<0.001）和3.85（95%CI:2.51-5.91，<0.001）。然而，两组肥大细胞的表型和分布不同：在FeNO高哮喘中，气道高反应性与浸润上皮层的糜蛋白酶高肥大细胞密度相关（ρ：-0.42 P=0.04），在FeNO低哮喘中，吸入皮质类固醇后气道高反应性的改善与肥大细胞以及气道TSLP和IL33的减少有关。
结论：气道对甘露醇的高反应性与哮喘表型中的肥大细胞浸润有关，与FeNO高哮喘的上皮肥大细胞和FeNO低哮喘的气道平滑肌肥大细胞有关。在两组患者中，吸入皮质类固醇治疗均能有效降低气道高反应性。
(中日友好医院呼吸与危重症医学科 李红雯 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2023 Mar 10;S0091-6749(23)00291-9. doi: 10.1016/j.jaci.2023.03.001.)
(J Allergy Clin Immunol. 2023 Mar 10;S0091-6749(23)00291-9. doi: 10.1016/j.jaci.2023.03.001.)
Airway Hyperresponsiveness Reflects Corticosteroid-Sensitive Mast Cell Involvement Across Asthma Phenotypes
Morten Hvidtfeldt, Asger Sverrild, Alexis Pulga, Laurits Frøssing, Alexander Silberbrandt, Morten Hostrup, Martin Thomassen, Caroline Sanden, Carl Magnus Clausson, Premkumar Siddhuraj, Daisy Bornesund, Juan Jose Nieto-Fontarigo, Lena Uller, Jonas Erjefält, Celeste Porsbjerg
Abstract
Background: Airway hyperresponsiveness is a hallmark of asthma across asthma phenotypes. Airway hyperresponsiveness to mannitol specifically relates to mast cell infiltration of the airways, suggesting inhaled corticosteroids to be effective in reducing the response to mannitol, despite low levels of type 2 inflammation.
Objective: The aim of the RECONSTRUCT study was to investigate the relationship between airway hyperresponsiveness and infiltrating mast cells, and the response to inhaled corticosteroid treatment.
Methods: In 50 corticosteroid-free patients with airway hyperresponsiveness to mannitol, mucosal cryobiopsies were obtained before and after 6 weeks daily treatment with 1600μg budesonide. Patients were stratified according to baseline FeNO with a cut-off of 25ppb.
Results: Airway hyperresponsiveness was comparable at baseline and improved equally with treatment in both FeNO-high and FeNO-low asthma: doubling dose: 3.98 (95% CI:2.49-6.38, P<0.001) and 3.85 (95% CI: 2.51-5.91, P<0.001), respectively. However, phenotypes and distribution of mast cells differed between the two groups: In FeNO-high asthma, Airway hyperresponsiveness correlated to the density of chymase high mast cells infiltrating the epithelial layer (ρ: -0.42 P= 0.04), and in FeNO-low asthma, to the density in airway smooth muscle (ρ: -0.51, P=0.02). The improvement in airway hyperresponsiveness after inhaled corticosteroids correlated with a reduction in mast cells, as well as in airway TSLP and IL33.
Conclusions: Airway hyperresponsiveness to mannitol is related to mast cell infiltration across asthma phenotypes, correlating with epithelial mast cells in FeNO-high asthma, and airway smooth muscle mast cells in FeNO-low asthma. Treatment with inhaled corticosteroids was effective in reducing airway hyperresponsiveness in both groups.
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