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Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases

Kell DB (2009) BMC Med Genomics.  2009 Jan;2: 2. doi: 10.1186/1755-8794-2-2. 

Web URL: Read this and related abstracts on PubMed here



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.


Iron is an essential mineral, required for blood oxygenation and many other vital functions.  However, iron needs to be very tightly regulated within the body and brain, because in its free form, it can combine with 'reactive oxygen species' (produced as part of normal energy metabolism), leading to a damaging and self-perpetuating cycle of oxidative stress and inflammation.

This review considers the evidence that poor regulation of iron is a key contributor to many age-related, degenerative health conditions - including cardiovascular diseases, dementia and other neurological disorders - all of which are known to involve chronic inflammation and oxidative stress.

By taking a 'systems' perspective, and combining existing evidence from many different fields of study, the author not only elucidates many of the complexities of iron storage, handling and transport within the body and brain, but also explains their relevance to a wide range of physical and mental health disorders - all of which involve persistent and self-reinforcing cycles of inflammation and oxidative stress that contribute to further damage and degeneration unless these processes can be brought under control.

This approach explains why multiple different factors need to be considered for the successful management of these conditions, including the many roles of iron, and the systems involved in its regulation. 

It also illustrates clearly why the idea that any substance in isolation has either 'antioxidant' or 'pro-oxidant' properties is overly simplistic if not misleading, and that the evaluation of both new and existing treatments needs to take into account the complexity and inter-relatedness of physiological systems and the biochemical processes needed to maintain them.

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