Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

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, etc...Comment: 159 pages, including 9 Figs and 2184 reference

The effect of acute hypoxia on heat shock protein 72 expression and oxidative stress in vivo

The inducible human stress protein HSP72 performs vital roles within the body at rest and during periods of stress. Recently, a previously disclosed quadratic trend in basal HSP72 expression was shown to be reliable and repeatable. The notion of a physiological stressor such as hypoxia disrupting this basal quadratic trend is an interesting one. Monocyte-expressed HSP72 and TBARS were determined every 3 h, over a 12-h period in 12 healthy male subjects on two separate days, with trial day one ascertaining control values. A hypoxic intervention consisting of 75 min at a simulated altitude of 2,980 m, commencing and ceasing at 0930 and 1045, respectively, was incorporated on trail day 2. The hypoxic condition induced significantly (elevated) HSP72 values at 1100 (P = 0.002), 1400 (P < 0.001), 1700 (P = 0.034) and 2000 (P = 0.041) compared to control. Significant increases in plasma TBARS were seen in the hypoxic condition compared to control at 1100 (P = 0.006) and 1400 (P = 0.032). The results demonstrate that a 75-min bout of normobaric hypoxia is sufficient to induce significant increases in HSP72 expression, which disrupts the basal quadratic trend shown by others and here in the control condition. This increase may be linked to the observed changes in oxidative stress. These results may provide a tool for manipulating basal monocyte HSP72 expression within human heat acclimation exercise protocols