Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom; Department of Pharmacy, University of Naples Federico II, Naples, Italy.
Pharmacol Res. 2020 Oct;160:105189. doi: 10.1016/j.phrs.2020.105189. Epub 2020 Sep 8.
Glucocorticosteroids are the first-line therapy for controlling airway inflammation in asthma. They bind intracellular glucocorticoid receptors to trigger increased expression of anti-inflammatory genes and suppression of pro-inflammatory gene activation in asthmatic airways. In the majority of asthma patients, inhaled glucocorticoids are clinically efficacious, improving lung function and preventing exacerbations. However, 5-10 % of the asthmatic population respond poorly to high dose inhaled and then systemic glucocorticoids. These patients form a category of severe asthma associated with poor quality of life, increased morbidity and mortality, and constitutes a major societal and health care burden. Inadequate therapeutic responses to glucocorticoid treatment is also reported in other inflammatory conditions such as rheumatoid arthritis and inflammatory bowel disease; however, asthma represents the most studied steroid-refractory disease. Several cellular and molecular events underlying glucocorticoid resistance in asthma have been identified involving abnormalities of glucocorticoid receptor signaling pathways. These events have been strongly related to immunological dysregulation, genetic, and environmental factors such as cigarette smoking or respiratory infections. A better understanding of the multiple mechanisms associated with glucocorticoid insensitivity in asthma phenotypes could improve quality of life for people with asthma but would also provide transferrable knowledge for other inflammatory diseases. In this review, we provide an update on the molecular mechanisms behind steroid-refractory asthma. Additionally, we discuss some therapeutic options for treating those asthmatic patients who respond poorly to glucocorticoid therapy.
糖皮质激素是控制哮喘气道炎症的一线治疗药物。它们与细胞内糖皮质激素受体结合，触发哮喘气道中抗炎基因的表达增加和促炎基因激活的抑制。在大多数哮喘患者中，吸入糖皮质激素具有临床疗效，可改善肺功能并预防加重。然而，5-10%的哮喘患者对高剂量吸入和全身糖皮质激素反应不佳。这些患者形成了一类与生活质量差、发病率和死亡率增加相关的严重哮喘，并构成了主要的社会和医疗保健负担。在其他炎症性疾病如类风湿关节炎和炎症性肠病中也报告了对糖皮质激素治疗反应不足的情况；然而，哮喘是研究最多的类固醇难治性疾病。已经确定了哮喘中糖皮质激素抵抗的几个细胞和分子事件，涉及糖皮质激素受体信号通路的异常。这些事件与免疫失调、遗传和环境因素（如吸烟或呼吸道感染）密切相关。更好地了解与哮喘表型中糖皮质激素不敏感相关的多种机制，可以提高哮喘患者的生活质量，但也为其他炎症性疾病提供了可转移的知识。在这篇综述中，我们提供了关于类固醇难治性哮喘背后的分子机制的最新信息。此外，我们还讨论了一些治疗那些对糖皮质激素治疗反应不佳的哮喘患者的治疗选择。
