Iron chelates bind nitric oxide and decrease mortality in an experimental model of septic shock.

Abstract

The hydroxamic acid siderophore ferrioxam- Nitric oxide (NO), a short-lived potent vasodilator, was first described as the endothelium-derived relaxation factor (EDRF) (1-3). The formation of NO from the guanidino nitrogen group of L-arginine is catalyzed by a group of enzymes termed constitutive (cNOs) and inducible (iNOs) NO synthases (3,4). The inducible form is not present constitutively in mammalian cells but is induced by proinflammatory stimuli such as bacterial lipopolysaccharide (LPS), Corynebacterium parvum, and the cytokines tumor necrosis factor-a, interleukin-1, or interferon-y, individually or in combination (5). Excess production of NO is reported to be associated with the development of hypotension associated with endotoxemia and sepsis (6-8).Inhibition of iNOs is a potential therapeutic approach to the treatment of septic shock (6-9). However, mechanisms to protect against the deleterious effects of NO overproduction constitute an alternative approach. For instance, free hemoglobin can scavenge NO and inhibit its biological effects (10). In LPS-treated mice, formation of a paramagnetic mononitrosyl iron complex with diethyldithiocarbamate (NO Fe DETC) was detected and characterized by electron paramagnetic resonance (11). The NO formed in this animal model was trapped with endogenous Fe2+ complexed with a considerable amount (500 mg/kg) of DETC that was administered to the animals during the course of the experiment (11). Mortality was not addressed in this study. On the other hand, administration of vitamin B12A to mice prevented and reversed endotoxinmediated hypotension and decreased mortality, possibly through binding of the vitamin with excess NO (12). Inhibition of several actions of NO, including protection of rats against endotoxin, was demonstrated with the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazolineoxyl-i-oxyl 3-oxide (13). We and others have characterized the in vivo models of induction of iNOs in mice and rats injected with C. parvum or C. parvum + LPS (14-18). We postulated that iron complexes could act as general NO scavengers and provide protection against septic shock. We screened a library of metal chelators and chelates and found that [Fe(III)

Burkholderia spp. Alter Pseudomonas aeruginosa Physiology through Iron Sequestration

“…Because both PA4467 and pvdL are known to be iron regulated, we confirmed that fusion I could be induced under iron-limiting conditions. We monitored fusion I ␤-galactosidase activity in medium with increasing concentrations of diethylenetriaminepentaacetic acid (DTPA), an iron-chelating agent (21). As predicted, iron limitation was sufficient to induce fusion I (Fig.…”

Cellular Non-heme Iron Content Is a Determinant of Nitric Oxide-mediated Apoptosis, Necrosis, and Caspase Inhibition

“…Intracellular Iron Regulates Apoptotic Cell Death by Inhibition of Caspase Activity-Hepatocytes are iron-rich compared with RAW264.7 cells, and it is known that NO readily reacts with non-heme iron to form iron-nitrosyl complexes (21,29). These complexes could, in turn, protect cells from NO-induced toxicity by either scavenging NO (29) or converting NO to a potent S-nitrosylating species (10,20).…”

“…These complexes could, in turn, protect cells from NO-induced toxicity by either scavenging NO (29) or converting NO to a potent S-nitrosylating species (10,20). To determine if iron content accounted for the difference in NO sensitivity between hepatocytes and the macrophage cell line, we preloaded RAW264.7 cells with iron.…”

Therapeutic benefits of antioxidants during sepsis: Is protection against oxidant-mediated tissue damage only half the story? *

“…Recent investigations designed to interrupt ROS formation in the context of sepsis using iron chelation strategies have met with varying degrees of success (11)(12). However, combined treatment with N-acetylcysteine (NAC), a scavenger of H 2 O 2 , and deferoxamine (DFX), an iron chelator, has not been tested, and as hypothesized by Dr. Ritter and colleagues, this combination would effectively interrupt cytotoxic ROS formation via the Fenton reaction during sepsis.…”