Gillissen A, Nowak D
Department of Internal Medicine, University Hospital Bergmannsheil, Ruhr-University, Bochum, Germany.
Respir Med. 1998 Apr;92(4):609-23. doi: 10.1016/s0954-6111(98)90506-6.
Reactive free oxygen radicals are known to play an important role in the pathogenesis of various lung diseases such as idiopathic pulmonary fibrosis (IPF), adult respiratory distress syndrome (ARDS) or cystic fibrosis (CF). They can originate from endogenous processes or can be part of exogenous exposures (e.g. ozone, cigarette smoke, asbestos fibres). Consequently, therapeutic enhancement of anti-oxidant defence mechanisms in these lung disorders seems a rational approach. In this regard, N-acetyl-L-cysteine (NAC) and ambroxol have both been frequently investigated. Because of its SH group, NAC scavenges H2O2 (hydrogen peroxide), .OH (hydroxol radical), and HOCl (hypochlorous acid). Furthermore, NAC can easily be deacetylated to cysteine, an important precursor of cellular glutathione synthesis, and thus stimulate the cellular glutathione system. This is most evident in pulmonary diseases characterized by low glutathione levels and high oxidant production by inflammatory cells (e.g. in IPF and ARDS). NAC is an effective drug in the treatment of paracetamol intoxication and may even be protective against side-effects of mutagenic agents. In addition NAC reduces cellular production of pro-inflammatory mediators (e.g. TNF-alpha, IL-1). Also, ambroxol [trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexane hydrochloride] scavenges oxidants (e.g. .OH, HOCl). Moreover, ambroxol reduces bronchial hyperreactivity, and it is known to stimulate cellular surfactant production. In addition, ambroxol has anti-inflammatory properties owing to its inhibitory effect on the production of cellular cytokines and arachidonic acid metabolites. For both substances effective anti-oxidant and anti-inflammatory function has been validated when used in micromolar concentrations. These levels are attainable in vivo in humans. This paper gives an up-to-date overview about the current knowledge of the hypothesis that oxidant-induced cellular damage underlies the pathogenesis of many human pulmonary diseases, and it discusses the feasibility of anti-oxidant augmentation therapy to the lung by using NAC or ambroxol.
已知反应性氧自由基在多种肺部疾病的发病机制中起重要作用，如特发性肺纤维化（IPF）、成人呼吸窘迫综合征（ARDS）或囊性纤维化（CF）。它们可源自内源性过程，也可是外源性暴露的一部分（如臭氧、香烟烟雾、石棉纤维）。因此，在这些肺部疾病中增强抗氧化防御机制的治疗方法似乎是合理的。在这方面，N-乙酰-L-半胱氨酸（NAC）和氨溴索都经常被研究。由于其巯基，NAC可清除过氧化氢（H2O2）、羟自由基（·OH）和次氯酸（HOCl）。此外，NAC可轻易脱乙酰化为半胱氨酸，这是细胞内谷胱甘肽合成的重要前体，从而刺激细胞谷胱甘肽系统。这在以谷胱甘肽水平低和炎症细胞产生高氧化剂为特征的肺部疾病中最为明显（如IPF和ARDS）。NAC是治疗对乙酰氨基酚中毒的有效药物，甚至可能对诱变剂的副作用有保护作用。此外，NAC可减少促炎介质的细胞产生（如肿瘤坏死因子-α、白细胞介素-1）。同样，氨溴索[反式-4-（2-氨基-3,5-二溴苄基氨基）-环己烷盐酸盐]可清除氧化剂（如·OH、HOCl）。此外，氨溴索可降低支气管高反应性，并且已知可刺激细胞表面活性剂的产生。此外，氨溴索因其对细胞因子和花生四烯酸代谢产物产生的抑制作用而具有抗炎特性。当以微摩尔浓度使用时，这两种物质的有效抗氧化和抗炎功能均已得到验证。这些浓度在人体体内是可以达到的。本文对氧化应激诱导的细胞损伤是许多人类肺部疾病发病机制基础这一假说的当前知识进行了最新综述，并讨论了使用NAC或氨溴索对肺部进行抗氧化增强治疗的可行性。
