Kim Chang Kon, Agrawal Devendra K
Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California 91766 USA.
Arch Intern Med Res. 2025;8(2):107-120. doi: 10.26502/aimr.0202. Epub 2025 Apr 11.
Glucocorticoids are the cornerstone of asthma therapy due to their potent anti-inflammatory action. However, a subset of severe asthmatics do not respond to the standard glucocorticoid treatment. Such phenomenon is referred to as glucocorticoid insensitivity (GCI). From a clinical point of view, GCI is characterized by the reduced therapeutic response with improvement of less than 10-15% in lung function parameters, such as FEV1, upon the administration of an adequate glucocorticoid dose. The mechanisms underlying GCI involve disrupted glucocorticoid receptor (GR) signaling, overexpression of the dominant-negative GRβ isoform, increased activity of pro-inflammatory transcription factors such as NF-κB and AP-1, and abnormal GR phosphorylation by kinases such as p38 MAPK. These altered molecular pathways undermine the anti-inflammatory effects of glucocorticoids on immune and structural airway cells, thus maintaining the chronicity of airway inflammation and remodeling. GCI can be of innate genetic origin, as in the case of GR mutations, or acquired through environmental exposures, including viral infections, smoking, and long-term exposure to pollutants in the environment. GCI represents a big challenge in the management of asthma, since a large proportion of cases do not achieve an adequate level of control with the standard treatment options. Recent advances in the understanding of the molecular mechanisms underlying GCI have enabled the development of novel therapeutic strategies, including biologic therapies targeting interleukin-5 and IL-13, Janus kinase inhibitors, and small-molecule drugs aimed at restoring GR function. This article presents a critical discussion on the current state of knowledge regarding the glucocorticoid resistance mechanisms in asthma, identifying the clinical effects of new therapeutic strategies, with special emphasis on the need for personalized treatment regimens to improve outcomes in glucocorticoid insensitivity.
由于其强大的抗炎作用，糖皮质激素是哮喘治疗的基石。然而，一部分重度哮喘患者对标准糖皮质激素治疗无反应。这种现象被称为糖皮质激素不敏感（GCI）。从临床角度来看，GCI的特征是在给予足够剂量的糖皮质激素后，肺功能参数（如第一秒用力呼气容积[FEV1]）的治疗反应降低，改善幅度小于10%-15%。GCI的潜在机制包括糖皮质激素受体（GR）信号传导中断、显性负性GRβ亚型的过表达、促炎转录因子（如核因子κB[NF-κB]和活化蛋白-1[AP-1]）的活性增加以及p38丝裂原活化蛋白激酶（p38 MAPK）等激酶对GR的异常磷酸化。这些改变的分子途径削弱了糖皮质激素对免疫和气道结构细胞的抗炎作用，从而维持气道炎症和重塑的慢性状态。GCI可能源于先天性遗传，如GR突变的情况，也可能通过环境暴露获得，包括病毒感染、吸烟以及长期暴露于环境污染物。GCI是哮喘管理中的一大挑战，因为很大一部分病例采用标准治疗方案无法达到充分的控制水平。对GCI潜在分子机制认识的最新进展使得能够开发新的治疗策略，包括靶向白细胞介素-5和白细胞介素-13的生物疗法、Janus激酶抑制剂以及旨在恢复GR功能的小分子药物。本文对哮喘中糖皮质激素抵抗机制的当前知识状态进行了批判性讨论，确定了新治疗策略的临床效果，特别强调需要个性化治疗方案以改善糖皮质激素不敏感患者的预后。
