Abstract：
Airway hyperresponsiveness (AHR) is a key clinical feature of asthma. The presence of AHR in people with asthma provides the substrate for bronchoconstriction in response to numerous diverse stimuli, contributing to airflow limitation and symptoms including breathlessness, wheeze, and chest tightness. Dysfunctional airway smooth muscle significantly contributes to AHR and is displayed as increased sensitivity to direct pharmacologic bronchoconstrictor stimuli, such as inhaled histamine and methacholine (direct AHR), or to endogenous mediators released by activated airway cells such as mast cells (indirect AHR). Research in in vivo human models has shown that the disrupted airway epithelium plays an important role in driving inflammation that mediates indirect AHR in asthma through the release of cytokines such as thymic stromal lymphopoietin and IL-33. These cytokines upregulate type 2 cytokines promoting airway eosinophilia and induce the release of bronchoconstrictor mediators from mast cells such as histamine, prostaglandin D2, and cysteinyl leukotrienes. While bronchoconstriction is largely due to airway smooth muscle contraction, airway structural changes known as remodeling, likely mediated in part by epithelial-derived mediators, also lead to airflow obstruction and may enhance AHR. In this review, we outline the current knowledge of the role of the airway epithelium in AHR in asthma and its implications on the wider disease. Increased understanding of airway epithelial biology may contribute to better treatment options, particularly in precision medicine.
摘要：
气道高反应性（AHR）是哮喘的关键临床特征。哮喘患者中AHR的存在为支气管收缩提供了基础，以应对许多不同的刺激。导致气流受限和症状，包括呼吸困难，喘息和胸闷。功能异常的气道平滑肌（ASM）显着有助于AHR，并表现为对直接药理学支气管收缩刺激的敏感性增加。如吸入组胺和乙酰甲胆碱（直接AHR），或由活化的气道细胞如肥大细胞释放的内源性介质(间接AHR)。体内人体模型的研究表明，气道上皮的破坏在驱动炎症中起重要作用，该炎症介导哮喘中的间接AHR，通过释放细胞因子如TSLP和IL-33。这些细胞因子上调2型细胞因子促进气道嗜酸性粒细胞增多，并诱导支气管收缩介质从肥大细胞如组胺的释放，前列腺素D2和半胱氨酸白三烯。虽然支气管收缩主要是由于ASM收缩，气道结构变化称为“重塑”，可能部分由上皮衍生的介质介导，还会导致气流阻塞，并可能增强AHR。在这次审查中,我们概述了目前关于气道上皮在哮喘AHR中的作用及其对更广泛疾病的影响的知识.增加对气道上皮生物学的了解可能有助于更好的治疗选择，特别是在精准医学领域。
