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

Multiscale modelling of fluid and drug transport in vascular tumours.

A model for fluid and drug transport through the leaky neovasculature and porous interstitium of a solid tumour is developed. The transport problems are posed on a micro-scale characterized by the inter-capillary distance, and the method of multiple scales is used to derive the continuum equations describing fluid and drug transport on the length scale of the tumour (under the assumption of a spatially periodic microstructure). The fluid equations comprise a double porous medium, with coupled Darcy flow through the interstitium and vasculature, whereas the drug equations comprise advection-reaction equations; in each case the dependence of the transport coefficients on the vascular geometry is determined by solving micro-scale cell problems

Multiscale modeling of fluid transport in tumors.

A model for fluid flow through the leaky neovasculature and porous interstitium of a solid tumor is developed. A network of isolated capillaries is analyzed in the limit of small capillary radius, and analytical expressions for the hydraulic conductivities and fractional leakage coefficients derived. This model is then homogenized to give a continuum description in terms of the vascular density. The resulting equations comprise a double porous medium with coupled Darcy flow through the interstitium and vasculature

A four‐compartment multiscale model of fluid and drug distribution in vascular tumours

The subtle relationship between vascular network structure and mass transport is vital to predict and improve the efficacy of anticancer treatments. Here, mathematical homogenisation is used to derive a new multiscale continuum model of blood and chemotherapy transport in the vasculature and interstitium of a vascular tumour. This framework enables information at a range of vascular hierarchies to be fed into an effective description on the length scale of the tumour. The model behaviour is explored through a demonstrative case study of a simplified representation of a dorsal skinfold chamber, to examine the role of vascular network architecture in influencing fluid and drug perfusion on the length scale of the chamber. A single parameter, P, is identified that relates tumour‐scale fluid perfusion to the permeability and density of the capillary bed. By fixing the topological and physiological properties of the arteriole and venule networks, an optimal value for P is identified, which maximises tumour fluid transport and is thus hypothesised to benefit chemotherapy delivery. We calculate the values for P for eight explicit network structures; in each case, vascular intervention by either decreasing the permeability or increasing the density of the capillary network would increase fluid perfusion through the cancerous tissue. Chemotherapeutic strategies are compared and indicate that single injection is consistently more successful compared with constant perfusion, and the model predicts optimal timing of a second dose. These results highlight the potential of computational modelling to elucidate the link between vascular architecture and fluid, drug distribution in tumours