B. S. Van Asbeck

Iron and inflammatory bowel disease

Both anaemia of iron deficiency and anaemia of chronic disease are frequently encountered in inflammatory bowel disease. Anaemia of iron deficiency is mostly due to inadequate intake or loss of iron. Anaemia of chronic disease probably results from decreased erythropoiesis, secondary to increased levels of proinflammatory cytokines, reactive oxygen metabolites and nitric oxide.

Iron chelation and hydroxyl radical scavenging reduce the inflammatory response of endothelial cells after infection with Chlamydia pneumoniae or influenza A

Background Chronic low‐grade inflammation is associated with increased risk of vascular diseases. The source of inflammation is unknown but may well be chronic and/or repetitive infections with microorganisms. Direct infection of endothelial cells (ECs) may also be a starting point for atherogenesis by initiating endothelial procoagulant activity, increased monocyte adherence and increased cytokine production. We hypothesized that iron‐mediated intracellular hydroxyl radical formation after infection is a key event in triggering the production of interleukin‐6 (IL‐6) by ECs in vitro.

Anti-HIV effect of iron chelators: different mechanisms involved

BACKGROUND Drugs for the treatment of AIDS have been directed to specific events in the human immunodeficiency virus (HIV-1) life cycle, aimed to stop viral replication by inhibition of reverse transcriptase or protease activity. Studies showing that oxidative stress and iron may be important in the activation of HIV-1 have focused attention on the potential therapeutic use of iron chelators. OBJECTIVES The goal of this review is to describe several possibilities as to how iron is involved in the replication of HIV and how iron chelation may interfere in this process. STUDY DESIGN First some physico-chemical properties of iron concerning solubility, oxidation-reduction potential, catalysis, and chelation will be discussed. In the second part, the role of iron in various biochemical systems is explained. RESULTS Nuclear factor kappa B (NF-kappaB) activation, regulating proviral transcription, can be influenced by iron through the production of reactive oxygen species. A second route by which iron chelation could influence HIV replication, is by inhibition of DNA synthesis through inactivation of iron-dependent ribonucleotide reductase. Another strategy which can be employed in targeting iron chelators against HIV-1, is direct oxidative viral RNA/DNA attack. This could be achieved by bleomycin, a cytostatic agent with the ability to form a complex with DNA and RNA. CONCLUSION Chelation may withhold iron from viral metabolism but on the other hand may also favor catalysis of reactive oxygen species directed to viral constituents. In combination with existing antivirals, iron chelation could add to improve the treatment of HIV-disease.

Glutathione and α‐lipoate in diabetic rats: nerve function, blood flow and oxidative state

Background Increased oxidative stress is considered to be a causal factor in the development of diabetic complications, among which peripheral neuropathy. The pathophysiology of nerve dysfunction in diabetes has been explained both by reduced endoneurial microcirculation and alterations in endoneurial metabolism. It is unclear whether antioxidants primarily improve nerve blood flow or normalise systemic or endoneurial oxidative metabolism. Therefore, we evaluated the effects of the antioxidants glutathione and α‐lipoic acid on both nerve microcirculation and the antioxidative capacity and lipid peroxidation in experimentally diabetic rats.

Effects of insulin treatment on endoneurial and systemic oxidative stress in relation to nerve conduction in streptozotocin-diabetic rats.

As increased oxidative stress is probably a pathogenetic factor in the development of diabetic complications, we studied nerve function and endogenous antioxidants in plasma, erythrocytes and sciatic nerve of untreated and insulin‐treated streptozotocin‐diabetic rats. After 18 weeks, the diabetes‐induced sciatic nerve conduction velocity deficits were approximately 65% improved by insulin (P<0.001). Plasma superoxide dismutase was significantly reduced in diabetes (P<0.01); smaller decreases in plasma catalase and glutathione levels were observed. These changes were corrected by insulin treatment. In erythrocytes, decreased superoxide dismutase (P<0.05) and increased total glutathione levels (P<0.05) were found. All effects of diabetes, including a rise in plasma malonyldialdehyde (P<0.05), were partially reversed by insulin treatment. In nervous tissue, diabetes caused increased catalase activity, uninfluenced by insulin (P<0.05). Nerve superoxide dismutase and glutathione did not change. The data suggest that, in diabetes, changes in systemic rather than endoneurial oxidative stress lead to nerve dysfunction.

Human immunodeficiency virus type 1 replication inhibition by the bidentate iron chelators CP502 and CP511 is caused by proliferation inhibition and the onset of apoptosis

The iron chelators deferoxamine (DF) and deferiprone (CP20) have been shown to inhibit human immunodeficiency virus type 1 (HIV‐1) replication in human peripheral blood lymphocytes (PBL). The orally active bidentate chelators CP502 and CP511, which also belong to the 3‐hydroxypyridin‐4‐one family, but with higher affinities for iron than CP20, were monitored for their antiviral properties by checking for p24 antigen production and nuclear factor (NF)‐κB activation, and their ability to induce apoptosis.

Oxygen Toxicity: Role of Hydrogen Peroxide and Iron

An important factor in tissue damage by toxic oxygen species is the ability to increase the level of hydrogen peroxide. This inter mediate of oxygen reduction is not only a precursor of species with a higher reactivity, such as the hydroxyl radical, but it also controls the process of inflammatation by its effect on the synthesis of vasoactive and chemotactic compounds. However, tissue injury by hydrogen peroxide often, if not always, depends on the availability of catalytic iron.

Iron enhances endothelial cell activation in response to Cytomegalovirus or Chlamydia pneumoniae infection.

Background  Chronic inflammation has been implemented in the pathogenesis of inflammatory diseases like atherosclerosis. Several pathogens like Chlamydia pneumoniae (Cp) and cytomegalovirus (CMV) result in inflammation and thereby are potentially artherogenic. Those infections could trigger endothelial activation, the starting point of the atherogenic inflammatory cascade. Considering the role of iron in a wide range of infection processes, the presence of iron may complicate infection‐mediated endothelial activation.

The effect of porphyrins on cellular redox systems: a study on the dark effect of porphyrins on phagocytes

Abstract. Erythropoietic protoporphyria (EPP) and porphyria cutanea tarda (PCT) are characterized by skin morbidity, induced by pro‐inflammatory reactive oxygen species generated by the photosensitizing properties of protoporphyrin IX and uroporphyrin I. How these porphyrins exert a toxic effect on the liver in the absence of light is poorly understood. We tested the hypothesis that porphyrins can interference with cellular redox systems, by studying the dark effects of protoporphyrin (PP), haematoporphyrin (HP), deu‐teroporphyrin (DP) and uroporphyrin (UP) on the cellular redox system of phagocytes, and on enzymatic oxyradical generating systems. Both in phagocytic cells and enzymatic systems, a dose‐dependent inhibition of chemiluminescence was observed by all porphyrins added. Catalase and SOD‐like activity of porphyrins was excluded by oxygraph and ferricyto‐chrome c reduction. However, ferrocytochrome c oxidation was inhibited by porphyrins indicating ferrireductase‐like activity. In a Fenton type reaction between H2O2 and PP, we could demonstrate the generation of *OH, or an electronically excited por‐phyrin species. No influence on phagocyte chemotaxis, phagocytosis and killing‐capacity was observed. We conclude that porphyrins do interfere with (cellular) redox systems and can both inhibit and enhance oxygen free radical generation, dependent on the type of redox reaction. Porphyrins can thus affect cellular metabolism. Since H2O2 and PP both readily dissolve in biological membranes, their interaction in the presence of transition metals may contribute to the toxic dark effects of porphyrins as observed in patients with EPP and PCT.

Therapy with Red Blood Cells Decreases Hyperoxic Pulmonary Injury

Results of attempts to ameliorate hyperoxic pulmonary injury using novel systems for delivery of antioxidant enzymes are reviewed. Intratracheal insufflation of either liposome encapsulated superoxide dismutase or encapsulated catalase increased levels of enzyme activities in rat lung homogenates and prevented lethal effects of an atmosphere of oxygen. Intact erythrocytes placed in the tracheobronchial tree of rats also dramatically improved survival in hyperoxia. Recyclable glutathione appeared to be the constituent of erythrocytes, which was responsible for the protection. In rabbits, erythrocytes also protected from oxidant-mediated ischemic-reoxygenation lung injury. These studies suggest a possible role for erythrocytes as biologic packets of antioxidant enzymes.