Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases.
Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases.
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DOI：
10.1186/1755-8794-2-2
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发表时间：
2009-01-08
影响因子：
2.7
通讯作者：
Kell DB
中科院分区：
文献类型：
--
作者：
Kell DB
过氧化物和超氧化物的产生是有氧代谢的不可避免的结果，虽然这些特定的“活性氧物质”（ROS）可以表现出许多生物学效应，但它们本身并不具有过度的反应性，因此它们在生理浓度下不会特别有害。然而，它们与配位不良的铁物质的反应可能导致催化产生非常活跃和危险的羟基自由基，这是非常有害的，也是慢性炎症的主要原因。我们审查了大量的和广泛的证据，这种组合的（苏）过氧化物和配位不良的铁在大量的生理和病理过程和炎症性疾病，特别是那些涉及细胞和有机体性能的逐步退化的参与。这些疾病有很多相似之处，因此可能被认为有一个共同的原因（即铁催化的自由基，尤其是羟基自由基的产生）。综述的研究包括那些专注于一系列心血管，代谢和神经系统疾病的研究，其中铁可以在斑块和病变部位找到，以及显示铁对衰老和长寿的重要性的研究。因此，通过天然或合成配体对铁的有效螯合具有主要的生理（和潜在的治疗）重要性。作为系统属性，我们需要认识到生理可观测值具有多个分子原因，当多个因素同时组合时，孤立地研究它们会导致明显因果关系的不一致模式。这解释了，例如，已经观察到的抗氧化剂的明显混合效应，因为在某些情况下（特别是存在配位不良的铁），名义上是抗氧化剂的分子实际上可以充当促氧化剂。因此，氧化还原应激的减少需要合适水平的抗氧化剂和有效的铁螯合剂。一些多酚类抗氧化剂可能同时具有这两种作用。因此，了解铁在所有状态下的确切形态和配体对于分离其各种促炎和抗炎活性至关重要。氧化还原应激、先天免疫和促炎性细胞因子（以及一些抗炎性细胞因子）特别是通过涉及NF-κ B和p38的信号传导途径联系在一起，其中铁的氧化作用似乎涉及IkappaB激酶（IKK）反应的上游。在许多情况下，有可能确定ROS和配位不良的铁协同作用和自催化作用的机制，导致难以控制的“失控”反应，除非同时处理多个作用位点。一些分子，如他汀类药物和促红细胞生成素，传统上与抗炎活性无关，确实具有“多效性”抗炎作用，这可能是有益的。总体而言，我们认为，通过合成一个广泛分散的文献，在过去，配位不佳的铁的作用一直是相当低估，并结合过氧化物和超氧化物的活性支撑的行为，随着时间的推移降解的很多生理过程。了解这些需要一个综合的，系统级的方法，可能会导致新的治疗目标。
The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular 'reactive oxygen species' (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, since in some circumstances (especially the presence of poorly liganded iron) molecules that are nominally antioxidants can actually act as pro-oxidants. The reduction of redox stress thus requires suitable levels of both antioxidants and effective iron chelators. Some polyphenolic antioxidants may serve both roles. Understanding the exact speciation and liganding of iron in all its states is thus crucial to separating its various pro- and anti-inflammatory activities. Redox stress, innate immunity and pro- (and some anti-)inflammatory cytokines are linked in particular via signalling pathways involving NF-kappaB and p38, with the oxidative roles of iron here seemingly involved upstream of the IkappaB kinase (IKK) reaction. In a number of cases it is possible to identify mechanisms by which ROSs and poorly liganded iron act synergistically and autocatalytically, leading to 'runaway' reactions that are hard to control unless one tackles multiple sites of action simultaneously. Some molecules such as statins and erythropoietin, not traditionally associated with anti-inflammatory activity, do indeed have 'pleiotropic' anti-inflammatory effects that may be of benefit here. Overall we argue, by synthesising a widely dispersed literature, that the role of poorly liganded iron has been rather underappreciated in the past, and that in combination with peroxide and superoxide its activity underpins the behaviour of a great many physiological processes that degrade over time. Understanding these requires an integrative, systems-level approach that may lead to novel therapeutic targets.
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