More antioxidants in sepsis: Still paved with uncertainties

10.1097/01.CCM.0000199051.33808.C3Critical Care Medicine342569-571CCMD

Functional defects in phagocytic cells from patients with iron overload

Phagocytic functions were studied in patients with iron overload. Phagocytosis of radiolabelled opsonised Staphylococcus aureus by mononuclear (MN) leucocytes and polymorphonuclear (PMN) leucocytes was measured in 15 and 16 patients, respectively. The intracellular killing capacity of MN and PMN leucocytes of seven and nine patients, respectively, and chemotaxis of PMN leucocytes of eight patients, were assessed also. These cellular functions were compared with phagocytic functions of controls tested on the same day, and with the normal ranges of phagocytic cell functions obtained with MN and PMN leucocytes from 48 and 59 healthy donors, respectively. One or more phagocytic functions were impaired in 62·5 per cent of the patients. Comparison of the various phagocytic functions in patients and simultaneously tested controls showed a significant decrease of the mean phagocytic capacity of the patients' MN and PMN leucocytes (P < 0·015 and P < 0·03, respectively), as well as the mean bactericidal activity of the MN leucocytes (P < 0·05) and the mean chemotactic responsiveness of the PMN leucocytes (P < 0·025). Patients with excess iron must be regarded as compromised hosts, not only because of the increased availability of iron for bacterial growth, but also because of the associated functional impairment of monocytes and granulocytes

High rat food vitamin E content improves nerve function in streptozotocin-diabetic rats

Antioxidants can improve nerve dysfunction in hyperglycaemic rats. We evaluated whether the standard supplementation of rat food with vitamin E (normally added for preservation purposes) or high-dose vitamin E treatment improves nerve conduction in maturing streptozotocin-diabetic rats, a model widely used to study diabetic neuropathy. Hyperglycaemic rats received food containing 25 mg/kg (non-supplemented), 70 mg/kg (standard food) or 12 g/kg (high-dose) vitamin E. Non-diabetic controls received non-supplemented food. Sciatic and tibial sensory and motor nerve conduction velocity were decreased in all diabetic animals. In comparison with standard feeding, the non-supplemented diabetic rats showed lower plasma vitamin E levels but no significant change in nerve conduction. High-dose treatment prevented nerve dysfunction by 50%, and led to attenuated endoneurial lipid peroxidation (measured as malondialdehyde). We conclude that high doses of vitamin E, but not standard vitamin E supplementation of rat food partially prevent nerve dysfunction in young adult streptozotocin-diabetic rats

Nerve conduction and antioxidant levels in experimentally diabetic rats: effects of streptozotocin dose and diabetes duration

Oxidative stress supposedly plays a role in the pathogenesis of diabetic neuropathy. We have studied whether a variation in the streptozotocin (STZ) dose or diabetes duration affects the outcome of measurements of oxidative damage in relation to nerve conduction. In experiment 1, we induced diabetes in rats using 40 or 60 mg/kg STZ intravenously and assessed sciatic nerve conduction velocity. After 18 weeks, we measured plasma malondialdehyde (MDA) and red blood cell (RBC) and nerve glutathione levels. We observed a dose-dependent effect of STZ on body weight, and to a lesser extent on nerve conduction, but not on RBC or nerve glutathione and plasma MDA. In experiment 2, we administered a fixed dose of STZ (40 mg/kg) and measured antioxidants and MDA in RBCs, plasma, and sciatic nerve after 2, 4, 8, and 18 weeks in diabetic and control rats. RBC glutathione decreased in diabetic animals initially, but did not differ from control values after week 4. Plasma total glutathione increased until week 8. The ratio of total to oxidized glutathione in the sciatic nerve from diabetic animals paralleled the decrease observed in RBCs, and subsequently increased compared with controls. Nerve catalase increased in diabetic animals. Endoneurial MDA remained unchanged, whereas plasma MDA increased and RBC superoxide dismutase (SOD) decreased in the diabetic group. We conclude that differences in antioxidant levels between STZ-diabetic and control rats depend on the duration of hyperglycemia. Furthermore, dose-related effects of STZ on nerve conduction are not reflected in endoneurial lipid peroxidation or glutathione

Nerve function and oxidative stress in diabetic and vitamin E deficient rats

Nerve dysfunction in diabetes is associated with increased oxidative stress. Vitamin E depletion also leads to enhanced presence of reactive oxygen species (ROS). We compared systemic and endoneurial ROS activity and nerve conduction in vitamin E-depleted control and streptozotocin-diabetic rats (CE− and DE−), and in normally fed control and diabetic animals (CE+ and DE+). Nerve conduction was reduced in both diabetic groups. Vitamin E depletion caused a small further nerve conduction deficit in the diabetic, but not in the control animals. The combination of vitamin E deficiency and streptozotocin-diabetes (group DE−) appeared to be lethal. In the remaining groups, an important rise in sciatic nerve malondialdehyde (MDA) was observed in the vitamin E-depleted control rats. In contrast, plasma MDA levels were elevated in group DE+ only, whereas hydrogen peroxide levels were increased in group CE−. Endoneurial total and oxidized glutathione and catalase were predominantly elevated in group DE+. These data show that nerve lipid peroxidation induced by vitamin E depletion does not lead to reduced nerve conduction or changes in antioxidant concentrations as observed in STZ-diabetes. The marked systemic changes in MDA and antioxidants suggest that nerve dysfunction in experimental hyperglycemia is rather a consequence of systemic than direct nerve damage

Endothelial activation and induction of monocyte adhesion by nontransferrin-bound iron present in human sera.

Contains fulltext : 49413.pdf (publisher's version ) (Closed access)Nontransferrin-bound iron (NTBI) has been detected in iron overload diseases. This form of iron may exert pro-oxidant effects and modulate cellular function and inflammatory response. The present study has aimed to investigate the effects of serum NTBI on monocyte adherence to endothelium. Measured by a recently developed high-throughput fluorescence-based assay, serum NTBI was found to be higher in both homozygotes of HFE C282Y mutation of hereditary hemochromatosis (7.9+/-0.6 microM, n=9, P<0.001) and heterozygotes (4.0+/-0.5 microM, n=8, P<0.001), compared with controls (1.6+/-0.2 microM, n=21). The effects of these sera on monocyte adhesion and endothelial activation were examined. Adhesion of normal human monocytes to C282Y homozygote- and heterozygote-serum-treated human umbilical vein endothelial cells was higher (25.0+/-0.9 and 22.1+/-0.7%, respectively) compared with controls (17.6+/-0.5%, both P<0.001). For the three groups combined, the expression of adhesion molecules, ICAM-1, VCAM-1, and E-selectin, was positively correlated to NTBI levels but not to the inflammatory marker C-reactive protein. Furthermore, accumulation of intracellular labile iron and oxidative radicals within the cells due to NTBI was evidenced. Finally, counteraction of NTBI-induced endothelial activation was observed using iron chelators. These findings therefore identify a physiological function of NTBI in monocyte-endothelial interactions that may also contribute to the development of atherosclerosis and neurodegenerative diseases