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

Thyrotropin stimulates production of procoagulant and vasodilatative factors in human aortic endothelial cells

Thyroid diseases have been associated with pathophysiological changes in the vasculature that may result from altered thyroid hormone production or to direct effect of elevated thyrotropin (TSH) levels on smooth muscle cells. A direct effect of TSH on vascular endothelium has not been considered. In the present study a strain of human aortic endothelial cells has been stimulated with TSH, and vascular parameters correlated with the atherosclerotic process have been analyzed. Addition of TSH induced an increase of cyclic AMP (cAMP) concentration in human aortic endothelial cells. Furthermore it induced a decrease of endothelin (from 30 +/- 2.5 to 13 +/- 1 fmol/mL) and of tissue plasminogen activator secretion (from 2,800 +/- 200 to 1,600 +/- 150 ng/mL). On the other hand, it increased nitric oxide (from 148 +/- 8 to 211 +/- 12 muM). TSH did not affect plasminogen activator inhibitor 1. Similar results were obtained when immunoglobulin Gs (IgGs) from Graves' disease patients were used. In conclusion, our findings suggest that TSH and IgGs from Graves' disease patients could stimulate endothelial cells, increasing the secretion of procoagulant and vasodilatative factors, and that cAMP is involved in the transduction pathway. These findings are consistent with modifications of the fibrinolytic system reported in hypothyroidism and in Graves' disease. On the other hand, the increase of vascular resistance found in patients with hypothyroidism may be due to the altered thyroid hormone production and not to TSH directly, or to a different effect of TSH on peripheral vessels

Antibodies that promote thyroid growth. A distinct population of thyroid-stimulating autoantibodies.

We used a strain of differentiated rat-thyroid cells in continuous culture (the FRTL-5 strain) to detect the presence of growth-promoting antibodies in serum samples from patients with autoimmune thyroid disease. We found that IgG preparations from 17 of 20 patients (85 per cent) with active Graves' disease and two of five patients (40 per cent) with Hashimoto's thyroiditis could augment thyroid-cell growth. In parallel with IgG-induced elevations in intracellular cyclic AMP levels in the same cell line, all 20 of the patients with active Graves' disease had thyroid-stimulatory antibodies. Patients' IgG preparations fell into three subclasses: those with both potent cyclic AMP stimulation and potent growth-promoting activity; those with potent cyclic AMP stimulation but low-level growth promotion; and those with potent growth promotion and low-level cyclic AMP action. Growth-promoting antibodies were not detected in patients with Graves' disease in remission (seven patients), nodular goiter (seven), subacute thyroiditis (five), or atrophic thyroiditis (one). Simultaneous assays of growth promotion and cyclic AMP stimulation may be useful in the care of patients with autoimmune thyroid disease