Lambers Christopher, Roth Michael
Department Pneumology, Ordensklinikum Linz Elisabethinen, AT-4020 Linz, Austria.
Pulmonary Cell Research, Department of Biomedicine & Clinic of Pneumology, University and University Hospital Basel, CH-4031 Basel, Switzerland.
Biomedicines. 2025 Jun 10;13(6):1418. doi: 10.3390/biomedicines13061418.
Glucocorticoid insensitivity is a problem for the therapy of chronic inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Both are non-communicable chronic inflammatory lung diseases with worldwide increasing incidences. Only symptoms can be controlled by inhaled or systemic glucocorticoids, often combined with β2 agonists and/or muscarinic receptor antagonists. The therapeutic effect of glucocorticoids varies between individuals, and a significant number of patients do not respond well. It is believed that only protein-free circulating unbound glucocorticoids can enter cells by diffusion and achieve their therapeutic effect by binding to the intracellular glucocorticoid receptor (GR), encoded by the NR3C1 gene, for which over 3000 single-nucleotide polymorphisms have been described. In addition, various GR protein isoforms result from 11 transcription start sites, and differential mRNA splicing leads to further GR protein variants; each can be modified post-translational and alter steroid response. To add more variety, some GR isoforms are expressed cell-type specific or in a sub-cellular location. The GR only functions when it forms a complex with other intracellular proteins that regulate ligand binding, cytosol-to-nuclear transport, and nuclear and cytosolic action. Importantly, the timing of the GR activity can be cell type, time, and condition specific. These factors are rarely considered when assessing disease-specific loss or reduced GR response. : Future studies should analyze the timing of the availability, activity, and interaction of all components of the glucocorticoid signaling cascade(s) and compare these factors between non-diseased and diseased probands, applying the combination of all omics methods (250).
糖皮质激素不敏感性是慢性炎症性肺部疾病（如哮喘和慢性阻塞性肺疾病（COPD））治疗中的一个问题。这两种疾病都是非传染性慢性炎症性肺部疾病，在全球范围内发病率不断上升。吸入或全身性糖皮质激素通常与β2激动剂和/或毒蕈碱受体拮抗剂联合使用，只能控制症状。糖皮质激素的治疗效果因人而异，相当一部分患者反应不佳。据信，只有无蛋白的循环游离糖皮质激素才能通过扩散进入细胞，并通过与由NR3C1基因编码的细胞内糖皮质激素受体（GR）结合来发挥其治疗作用，已描述了该基因的3000多个单核苷酸多态性。此外，11个转录起始位点产生了各种GR蛋白异构体，不同的mRNA剪接导致了更多的GR蛋白变体；每种变体都可以进行翻译后修饰并改变类固醇反应。更复杂的是，一些GR异构体在细胞类型特异性或亚细胞位置表达。GR只有在与其他调节配体结合、胞质溶胶到细胞核转运以及核和胞质作用的细胞内蛋白质形成复合物时才起作用。重要的是，GR活性的时间可以是细胞类型、时间和条件特异性的。在评估疾病特异性GR反应丧失或降低时，很少考虑这些因素。未来的研究应分析糖皮质激素信号级联所有成分的可用性、活性和相互作用的时间，并应用所有组学方法的组合，比较非患病和患病先证者之间的这些因素（250）。
