Iron and 8-Isoprostane Levels in Acute and Chronic Wounds

Abstract

The purpose of this study was to determine differences in iron and iron protein (ferritin and transferrin) levels in chronic venous ulcers and acute wounds. The deleterious effect of iron in free-radical-induced tissue damage was indirectly examined by assessing 8-isoprostane levels and antioxidant status in wound fluid samples. Wound fluid samples from chronic leg ulcers in nonhealing and healing phases and wound fluid from mastectomy wounds were assayed for ferritin, transferrin, total iron, 8-isoprostane, and total antioxidant status. Immunohistochemistry and Perls' staining were performed on paired biopsies from chronic leg ulcers and on normal skin biopsies. Chronic wound fluid had significantly greater levels of ferritin (p < 0.05) and lower levels of transferrin (p < 0.001) than acute wound fluid and there was a significant reduction in the level of ferritin in healing compared to nonhealing chronic leg ulcers (p < 0.05). No significant differences were observed in the levels of total iron present in the wound fluids. Histologic staining showed consistently more ferritin and ferric iron in chronic wound tissue than in normal skin. Elevated levels of 8-isoprostane and antioxidants were observed for chronic wound fluid compared to acute wound fluid (p < 0.001). These results suggest the existence of an environment of oxidative stress in chronic wounds and the likely contribution of iron to exacerbating tissue damage and delaying healing in these wounds.

Failure of the vascular hypothesis of multiple sclerosis in a rat model of chronic cerebrospinal venous insufficiency

“…Studies showed that chronic venous disease typically leads to iron deposition in tissues [1,48], which is in accordance with the present study.…”

“…Bilateral jugular vein stenosis in CCSVI was associated with activation of the cervical and intracranial collateral circles shunting the blood towards the superior vena cava and the azygos venous system, respectively [48]. The activation of these collateral circuits was confirmed by CT venogram in the JVL animal model used by Atkinson et al [3]; in the present study, the rat model was used replacing the original mouse model, the cerebral venous drainage in both species is similar as well as the brain structure with few minor differences [29,44].…”

An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice

“…This contributes to an up to 20-fold higher iron concentration in the lower limbs of CVU patients than in the upper arms of the same patients (25). Iron overload in tissue and wound exudates of CVUs, but not of acute wounds (AWs), was confirmed in 2 independent studies (18,19). In the presence of H 2 O 2 released by macrophages and neutrophils, iron drives the generation of highly toxic hydroxyl radicals (OH • ) via the Fenton reaction.…”

“…So far, there is evidence that venous hypertension - caused by venous valve incompetence - results in venous stasis of the lower extremity, low or absent shear stress, and hypoxia, which all trigger endothelial cell activation with "trapping" of monocytes/macrophages and other leukocytes in the microcirculation (13)(14)(15). Activated monocytes/macrophages and other leukocytes transmigrate into the tissue and release high amounts of proinflammatory cytokines (16), proteases (17), and ROS (18,19), which are responsible for the breakdown of the connective tissue and of essential growth factors (20)(21)(22), eventually leading to ulcer formation (1, 2, 9).…”

“…In the presence of H 2 O 2 released by macrophages and neutrophils, iron drives the generation of highly toxic hydroxyl radicals (OH • ) via the Fenton reaction. In fact, significant oxidative damage was found in CVUs (18,19). The pathogenic role of iron-overloaded macrophages in the perpetuated inflammatory nonhealing state of CVUs is poorly understood.…”