Department of Chest Disease, Strasbourg University Hospital, 1, place de l'Hôpital, 67091 Strasbourg, France; EA 3072, University of Strasbourg, France.
UMR 7200 CNRS/Université de Strasbourg, Laboratoire d'Innovation Thérapeutique and LabEx MEDALIS, Faculté de Pharmacie, Strasbourg, France.
Pharmacol Ther. 2018 Jun;186:98-113. doi: 10.1016/j.pharmthera.2018.01.004. Epub 2018 Jan 20.
Asthma is a chronic disorder characterized by persistent inflammation of the airways with mucosal infiltration of eosinophils, T lymphocytes, and mast cells, and release of proinflammatory cytokines and lipid mediators. The natural resolution of airway inflammation is now recognized as an active host response, with highly coordinated cellular events under the control of endogenous pro-resolving mediators that enable the restoration of tissue homeostasis. Lead members of proresolving mediators are enzymatically derived from essential polyunsaturated fatty acids, including arachidonic acid-derived lipoxins, eicosapentaenoic acid-derived E-series resolvins, and docosahexaenoic acid-derived D-series resolvins, protectins, and maresins. Functionally, these specialized pro-resolving mediators can limit further leukocyte recruitment, induce granulocyte apoptosis, and enhance efferocytosis by macrophages. They can also switch macrophages from classical to alternatively activated cells, promote the return of non-apoptotic cells to lymphatics and blood vessels, and help initiate tissue repair and healing. In this review, we highlight cellular and molecular mechanisms for successful resolution of inflammation, and describe the main specialized pro-resolving mediators that drive these processes. Furthermore, we report recent data suggesting that the pathobiology of severe asthma may result in part from impaired resolution of airway inflammation, including defects in the biosynthesis of these specialized pro-resolving mediators. Finally, we discuss resolution-based therapeutic perspectives.
哮喘是一种慢性疾病，其特征是气道持续炎症，黏膜中有嗜酸性粒细胞、T 淋巴细胞和肥大细胞浸润，并释放促炎细胞因子和脂质介质。目前认为气道炎症的自然消退是一种活跃的宿主反应，具有高度协调的细胞事件，受内源性促解决介质的控制，这些介质可恢复组织的体内平衡。促解决介质的主要成员是从必需多不饱和脂肪酸中酶解衍生而来的，包括花生四烯酸衍生的脂氧素、二十碳五烯酸衍生的 E 系列 resolvins 和二十二碳六烯酸衍生的 D 系列 resolvins、保护素和maresin。在功能上，这些特殊的促解决介质可以限制白细胞的进一步募集，诱导粒细胞凋亡，并增强巨噬细胞的吞噬作用。它们还可以使巨噬细胞从经典型向替代性激活细胞转变，促进非凋亡细胞向淋巴管和血管的返回，并有助于启动组织修复和愈合。在这篇综述中，我们强调了成功解决炎症的细胞和分子机制，并描述了驱动这些过程的主要特殊促解决介质。此外，我们报告了最近的数据表明，严重哮喘的病理生物学可能部分是由于气道炎症的解决受损，包括这些特殊促解决介质的生物合成缺陷。最后，我们讨论了基于解决的治疗观点。
