衣康酸在吸入性过敏原激发过程中的保护性作用
2025/10/31
摘要
背景：哮喘是一种以气道重塑、炎症和黏液产生为特征的慢性异质性疾病。气道巨噬细胞的功能以细胞代谢的变化为基础。TCA（三羧酸）循环衍生的代谢产物衣康酸（其合成由乌头酸脱羧酶介导）是巨噬细胞功能的关键调节因子；然而，其在吸入性过敏原激发过程中的作用尚不清楚。本研究的目的旨在明确衣康酸在吸入性过敏原激发过程中的作用。
方法：研究人员测量了接受过敏原吸入激发的轻度过敏性哮喘患者的痰液代谢物水平，并在第二个队列中（包括轻度、中度和重度哮喘患者）测量了其基线水平。此外，在野生型和乌头酸脱羧酶缺陷型小鼠，或在接受吸入性衣康酸治疗的小鼠中，评估了其气道炎症、肺功能和支气管肺泡灌洗液的代谢物水平。
结果：轻度哮喘患者吸入过敏原导致痰液中衣康酸水平显著降低。当比较健康对照组与轻度、中度和重度哮喘患者时，我们未发现其基线痰液衣康酸水平存在差异。野生型和乌头酸脱羧酶缺陷型小鼠在持续暴露于空气过敏原 48 小时、1 周、3 周或 5 周后，疾病表型未显示任何变化。使用吸入性衣康酸治疗暴露于尘螨的小鼠，减轻了其气道炎症。
结论：在轻度哮喘患者和疾病鼠类模型中，衣康酸水平在过敏原激发后发生了改变。在所有测试的时间点，衣康酸缺乏并未改变由尘螨诱导的病理变化；然而，吸入性衣康酸减轻了机体对吸入性过敏原的炎症反应。
Protective Role for Itaconate During Inhaled Allergen Challenge
Albers, G. J., Ogger, P. P., Michalaki, C., Stölting, H., Walker, S. A., Caldwell, A., Halket, J. M., Duvall, K., Batool, A., Joshi, L., O'Brien, H., McCarthy, C., Hinks, T., Gauvreau, G. M., O'Byrne, P. M., Lloyd, C. M., & Byrne, A. J.
Abstract
BACKGROUND:
Asthma is a chronic, heterogeneous disease characterised by airway remodelling, inflammation, and mucus production. Airway macrophages' functions are underpinned by changes in cellular metabolism. The TCA cycle-derived metabolite itaconic acid (whose synthesis is mediated by aconitate decarboxylase) is a master regulator of macrophage function; however, its role during inhaled allergen challenge is not clear. The objective of this study was to define the role of itaconate during inhaled allergen challenge.
METHODS:
Sputum metabolite levels were measured in participants with mild allergic asthma undergoing allergen inhalation challenge, and in a second cohort, baseline levels in mild, moderate, and severe asthmatics. Airway inflammation, lung function, and bronchoalveolar lavage metabolite levels were assessed in wild-type and aconitate decarboxylase-deficient mice, or in mice treated with inhaled itaconate.
RESULTS:
Allergen inhalation in mild asthmatics led to a significant reduction in sputum itaconate. We found no difference in baseline sputum itaconate levels when comparing healthy controls to mild, moderate, or severe asthmatics. Continuous exposure to aeroallergen in wild type and aconitate decarboxylase-deficient mice showed no change in disease phenotype after 48 h, 1, 3, or 5 weeks of allergen exposure. Treatment of house dust mite-exposed mice with inhaled itaconate reduced airway inflammation.
CONCLUSION:
Levels of itaconate are altered after allergen challenge in mild asthmatics and in murine models of disease. Itaconate deficiency did not alter house dust mite-induced pathology at any of the timepoints tested; however, inhaled itaconate ameliorated inflammatory responses to inhaled allergen.
背景：哮喘是一种以气道重塑、炎症和黏液产生为特征的慢性异质性疾病。气道巨噬细胞的功能以细胞代谢的变化为基础。TCA（三羧酸）循环衍生的代谢产物衣康酸（其合成由乌头酸脱羧酶介导）是巨噬细胞功能的关键调节因子；然而，其在吸入性过敏原激发过程中的作用尚不清楚。本研究的目的旨在明确衣康酸在吸入性过敏原激发过程中的作用。
方法：研究人员测量了接受过敏原吸入激发的轻度过敏性哮喘患者的痰液代谢物水平，并在第二个队列中（包括轻度、中度和重度哮喘患者）测量了其基线水平。此外，在野生型和乌头酸脱羧酶缺陷型小鼠，或在接受吸入性衣康酸治疗的小鼠中，评估了其气道炎症、肺功能和支气管肺泡灌洗液的代谢物水平。
结果：轻度哮喘患者吸入过敏原导致痰液中衣康酸水平显著降低。当比较健康对照组与轻度、中度和重度哮喘患者时，我们未发现其基线痰液衣康酸水平存在差异。野生型和乌头酸脱羧酶缺陷型小鼠在持续暴露于空气过敏原 48 小时、1 周、3 周或 5 周后，疾病表型未显示任何变化。使用吸入性衣康酸治疗暴露于尘螨的小鼠，减轻了其气道炎症。
结论：在轻度哮喘患者和疾病鼠类模型中，衣康酸水平在过敏原激发后发生了改变。在所有测试的时间点，衣康酸缺乏并未改变由尘螨诱导的病理变化；然而，吸入性衣康酸减轻了机体对吸入性过敏原的炎症反应。
（中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校）
（Allergy. 2025 Oct 24; DOI: 10.1111/all.70107）
（Allergy. 2025 Oct 24; DOI: 10.1111/all.70107）
Protective Role for Itaconate During Inhaled Allergen Challenge
Albers, G. J., Ogger, P. P., Michalaki, C., Stölting, H., Walker, S. A., Caldwell, A., Halket, J. M., Duvall, K., Batool, A., Joshi, L., O'Brien, H., McCarthy, C., Hinks, T., Gauvreau, G. M., O'Byrne, P. M., Lloyd, C. M., & Byrne, A. J.
Abstract
BACKGROUND:
Asthma is a chronic, heterogeneous disease characterised by airway remodelling, inflammation, and mucus production. Airway macrophages' functions are underpinned by changes in cellular metabolism. The TCA cycle-derived metabolite itaconic acid (whose synthesis is mediated by aconitate decarboxylase) is a master regulator of macrophage function; however, its role during inhaled allergen challenge is not clear. The objective of this study was to define the role of itaconate during inhaled allergen challenge.
METHODS:
Sputum metabolite levels were measured in participants with mild allergic asthma undergoing allergen inhalation challenge, and in a second cohort, baseline levels in mild, moderate, and severe asthmatics. Airway inflammation, lung function, and bronchoalveolar lavage metabolite levels were assessed in wild-type and aconitate decarboxylase-deficient mice, or in mice treated with inhaled itaconate.
RESULTS:
Allergen inhalation in mild asthmatics led to a significant reduction in sputum itaconate. We found no difference in baseline sputum itaconate levels when comparing healthy controls to mild, moderate, or severe asthmatics. Continuous exposure to aeroallergen in wild type and aconitate decarboxylase-deficient mice showed no change in disease phenotype after 48 h, 1, 3, or 5 weeks of allergen exposure. Treatment of house dust mite-exposed mice with inhaled itaconate reduced airway inflammation.
CONCLUSION:
Levels of itaconate are altered after allergen challenge in mild asthmatics and in murine models of disease. Itaconate deficiency did not alter house dust mite-induced pathology at any of the timepoints tested; however, inhaled itaconate ameliorated inflammatory responses to inhaled allergen.
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