Rahman I, MacNee W
ELEGI & Colt Laboratories, University of Edinburgh, Medical School, UK.
Eur Respir J. 2000 Sep;16(3):534-54. doi: 10.1034/j.1399-3003.2000.016003534.x.
Inflammatory lung diseases are characterized by chronic inflammation and oxidant/antioxidant imbalance, a major cause of cell damage. The development of an oxidant/antioxidant imbalance in lung inflammation may activate redox-sensitive transcription factors such as nuclear factor-KB, and activator protein-1 (AP-1), which regulate the genes for pro-inflammatory mediators and protective antioxidant genes. Glutathione (GSH), a ubiquitous tripeptide thiol, is a vital intra- and extracellular protective antioxidant against oxidative/nitrosative stresses, which plays a key role in the control of pro-inflammatory processes in the lungs. Recent findings have suggested that GSH is important in immune modulation, remodelling of the extracellular matrix, apoptosis and mitochondrial respiration. The rate-limiting enzyme in GSH synthesis is gamma-glutamylcysteine synthetase (gamma-GCS). The human gamma-GCS heavy and light subunits are regulated by AP-1 and antioxidant response elements and are modulated by oxidants, phenolic antioxidants, growth factors, and inflammatory and anti-inflammatory agents in lung cells. Alterations in alveolar and lung GSH metabolism are widely recognized as a central feature of many inflammatory lung diseases such as idiopathic pulmonary fibrosis, acute respiratory distress syndrome, cystic fibrosis and asthma. The imbalance and/or genetic variation in antioxidant gamma-GCS and pro-inflammatory versus antioxidant genes in response to oxidative stress and inflammation in some individuals may render them more susceptible to lung inflammation. Knowledge of the mechanisms of GSH regulation and balance between the release and expression of pro- and anti-inflammatory mediators could lead to the development of novel therapies based on the pharmacological manipulation of the production as well as gene transfer of this important antioxidant in lung inflammation and injury. This review describes the redox control and involvement of nuclear factor-kappaB and activator protein-1 in the regulation of cellular glutathione and gamma-glutamylcysteine synthetase under conditions of oxidative stress and inflammation, the role of glutathione in oxidant-mediated susceptibility/tolerance, gamma-glutamylcysteine synthetase genetic susceptibility and the potential therapeutic role of glutathione and its precursors in protecting against lung oxidant stress, inflammation and injury.
炎症性肺病的特征是慢性炎症以及氧化/抗氧化失衡，这是细胞损伤的主要原因。肺部炎症中氧化/抗氧化失衡的发展可能会激活氧化还原敏感的转录因子，如核因子-κB和激活蛋白-1（AP-1），它们可调节促炎介质基因和保护性抗氧化基因。谷胱甘肽（GSH）是一种普遍存在的三肽硫醇，是一种重要的细胞内和细胞外保护性抗氧化剂，可抵抗氧化/亚硝化应激，在控制肺部促炎过程中起关键作用。最近的研究结果表明，GSH在免疫调节、细胞外基质重塑、细胞凋亡和线粒体呼吸中具有重要作用。GSH合成中的限速酶是γ-谷氨酰半胱氨酸合成酶（γ-GCS）。人类γ-GCS重链和轻链亚基受AP-1和抗氧化反应元件调控，并受到肺细胞中的氧化剂、酚类抗氧化剂、生长因子以及炎症和抗炎剂的调节。肺泡和肺GSH代谢的改变被广泛认为是许多炎症性肺病（如特发性肺纤维化、急性呼吸窘迫综合征、囊性纤维化和哮喘）的核心特征。在某些个体中，抗氧化γ-GCS以及促炎基因与抗氧化基因在应对氧化应激和炎症时的失衡和/或基因变异可能使他们更容易患肺部炎症。了解GSH调节机制以及促炎和抗炎介质释放与表达之间的平衡，可能会基于对这种重要抗氧化剂在肺部炎症和损伤中的产生进行药理操作以及基因转移，开发出新的治疗方法。本综述描述了在氧化应激和炎症条件下，核因子-κB和激活蛋白-1的氧化还原控制及其在调节细胞谷胱甘肽和γ-谷氨酰半胱氨酸合成酶中的作用，谷胱甘肽在氧化剂介导的易感性/耐受性中的作用，γ-谷氨酰半胱氨酸合成酶的遗传易感性以及谷胱甘肽及其前体在预防肺部氧化应激、炎症和损伤方面的潜在治疗作用。
