Walsh G M, Sexton D W, Blaylock M G
Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.
J Endocrinol. 2003 Jul;178(1):37-43. doi: 10.1677/joe.0.1780037.
Anti-inflammatory therapy in asthma is reliant on corticosteroids, particularly in their inhaled form. However, steroids are rather non-specific in their actions and they also raise concerns regarding compliance and side-effect Issues. Furthermore, a small proportion of patients with asthma fail to respond to oral glucocorticoids even at high doses. This Article will review the role that steroids and membrane receptor ligation play in the induction of eosinophil apoptosis together with the mechanisms by which corticosteroids enhance the disposal of apoptotic eosinophils by both professional and non-professional phagocytes. Eosinophils are thought to be the major pro-inflammatory effector cell in asthma and their persistence in the airways is probably enhanced by the presence of several asthma-relevant cytokines that prolong eosinophil survival by inhibition of apoptosis (interleukin (IL)-3, IL-5, granulocyte-macrophage colony-stimulating factor, IL-9, IL-13, IL-15). In contrast, a number of signals have been described that accelerate apoptosis in human eosinophils including corticosteroids or ligation of membrane receptors (CD95, CD45, CD69). Thus, the load of lung eosinophils in asthmatic disease is likely to be related to a balance in the tIssue microenvironment between pro- and anti-apoptotic signals. Furthermore, removal of apoptotic eosinophils by phagocytosis by alveolar macrophages or bronchial epithelial cells in a specific receptor-mediated way is as important as the process of apoptosis induction. Corticosteroids enhance the recognition and engulfment of apoptotic eosinophils by macrophages or bronchial epithelial cells. Caspases are key intracellular molecules in the control of apoptosis and defects in caspase-induced apoptosis in eosinophils from steroid-resistant individuals may contribute to the molecular mechanisms underlying glucocorticoid insensitivity in these cells. These findings point the way to new and more targeted anti-inflammatory therapy for asthma and may provide important clues for the development of alternative therapies for glucocorticoid resistance.
哮喘的抗炎治疗依赖于皮质类固醇，尤其是吸入型皮质类固醇。然而，类固醇的作用相当非特异性，并且它们还引发了关于依从性和副作用问题的担忧。此外，一小部分哮喘患者即使高剂量口服糖皮质激素也无反应。本文将综述类固醇和膜受体结合在诱导嗜酸性粒细胞凋亡中所起的作用，以及皮质类固醇增强专业和非专业吞噬细胞对凋亡嗜酸性粒细胞清除的机制。嗜酸性粒细胞被认为是哮喘中主要的促炎效应细胞，气道中几种与哮喘相关的细胞因子的存在可能会增强它们的持久性，这些细胞因子通过抑制凋亡（白细胞介素（IL）-3、IL-5、粒细胞-巨噬细胞集落刺激因子、IL-9、IL-13、IL-15）来延长嗜酸性粒细胞的存活。相反，已经描述了一些加速人类嗜酸性粒细胞凋亡的信号，包括皮质类固醇或膜受体（CD95、CD45、CD69）的结合。因此，哮喘疾病中肺嗜酸性粒细胞的负荷可能与组织微环境中促凋亡和抗凋亡信号之间的平衡有关。此外，肺泡巨噬细胞或支气管上皮细胞以特定受体介导的方式吞噬凋亡嗜酸性粒细胞，与凋亡诱导过程同样重要。皮质类固醇增强巨噬细胞或支气管上皮细胞对凋亡嗜酸性粒细胞的识别和吞噬。半胱天冬酶是细胞内控制凋亡的关键分子，类固醇抵抗个体的嗜酸性粒细胞中半胱天冬酶诱导凋亡的缺陷可能是这些细胞中糖皮质激素不敏感的分子机制之一。这些发现为哮喘新的、更具针对性的抗炎治疗指明了方向，并可能为糖皮质激素抵抗替代疗法的开发提供重要线索。
