N??-NITRO-l-ARGININE METHYL ESTER EFFECTS ON NEUTROPHIL FUNCTION AND BACTERIAL CLEARANCE

Stehr, Sebastian; Weber, Sören; Heller, Susanne; Weikel, J.; Hübler, Matthias; Koch, Thea; Heller, A. R.

doi:10.1097/01.shk.0000132487.89800.15

Cited by 10 publications

(6 citation statements)

References 38 publications

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“…The latter was confirmed by our tests of three different NO donors. Some studies have actually reported inhibition of the oxidative burst in macrophages by NO donors (Lee et al 2002;Von Knethen and Brune 2002), even in vivo (Stehr et al 2004). Indeed, evidence suggests that iNOS induction is secondary to the respiratory burst (Fries et al 2003;Alblas et al 2005).…”

Section: Discussionmentioning

confidence: 99%

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Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation

Barger

Goodwin²,

Porter³

et al. 2007

Journal of Neurochemistry

218

170

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When activated by proinflammatory stimuli, microglia release substantial levels of glutamate, and mounting evidence suggests this contributes to neuronal damage during neuroinflammation. Prior studies indicated a role for the Xc exchange system, an amino acid transporter that antiports glutamate for cystine. Because cystine is used for synthesis of glutathione (GSH) synthesis, we hypothesized that glutamate release is an indirect consequence of GSH depletion by the respiratory burst, which produces superoxide from NADPH oxidase. Microglial glutamate release triggered by lipopolysaccharide was blocked by diphenylene iodonium chloride and apocynin, inhibitors of NADPH oxidase. This glutamate release was also blocked by vitamin E and elicited by lipid peroxidation products 4-hydroxynonenal and acrolein, suggesting that lipid peroxidation makes crucial demands on GSH.Although NADPH oxidase inhibitors also suppressed nitrite accumulation, vitamin E did not; moreover, glutamate release was largely unaffected by nitric oxide donors, inhibitors of nitric oxide synthase, or changes in gene expression. These findings indicate that a considerable degree of the neurodegenerative consequences of neuroinflammation may result from conversion of oxidative stress to excitotoxic stress. This phenomenon entails a biochemical chain of events initiated by a programmed oxidative stress and resultant mass-action amino acid transport. Indeed, some of the neuroprotective effects of antioxidants may be due to interference with these events rather than direct protection against neuronal oxidation.

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Section: Discussionmentioning

confidence: 99%

“…Some studies have actually reported inhibition of the oxidative burst in macrophages by NO donors (Lee et al. 2002; Von Knethen and Brune 2002), even in vivo (Stehr et al. 2004).…”

Section: Discussionmentioning

confidence: 99%

Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation

Barger

Goodwin²,

Porter³

et al. 2007

Journal of Neurochemistry

218

170

View full text Add to dashboard Cite

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“…Single‐cell analysis was performed by laser flow cytometry. The method of the quantitative assay for monitoring the oxidative burst has previously been described in detail 15, 17…”

Section: Methodsmentioning

confidence: 99%

IgM‐enriched solution BT086 improves host defense capacity and energy store preservation in a rabbit model of endotoxemia

Shmygalev

Damm

Knels

et al. 2015

Acta Anaesthesiol Scand

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IntroductionThe therapeutic value of intravenous immunoglobulin (IVIG) as an adjuvant therapy in sepsis remains debatable. We hypothesized that intravenous administration of BT086, a predominantly IgM IVIG solution, would improve host defense in an established rabbit model of endotoxemia and systemic sepsis.MethodsNew Zealand white rabbits were randomized into the following four groups: (1) the negative control group without lipopolysaccharide (LPS, control), (2) the positive control group with LPS infusion (LPS group), (3) the albumin‐treated LPS group (ALB+LPS group), and (4) the BT086‐treated LPS group (BT086 + LPS group). A standardized amount of E. coli was intravenously injected into all of the animals. The vital parameters, the concentration of E. coli in the blood and other organs, the residual granulocyte phagocytosis activity, and the levels of the inflammatory mediators were measured. Histological changes in the lung and liver tissue were examined following autopsy.ResultsThe elimination of E. coli from the bloodstream was expedited in the BT086‐treated group compared with the LPS‐ and albumin‐treated groups. The BT086 + LPS group exhibited higher phagocytic activity of polymorphonuclear neutrophils (PMNs) than the control and ALB+LPS groups. The liver energy stores were higher in the BT086 + LPS group than in the other groups.ConclusionOur data suggest that the IgM‐enriched IVIG has the potential to improve host defense in a rabbit model of endotoxemia. Studies using different animal models and dosages are necessary to further explore the potential benefits of IgM‐enriched IVIG solutions.

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“…Although both iNOS and nNOS have been implicated in several disease states, NOS inhibitors are not currently used for the treatment of any disorder, and studies that have examined the use of NOS inhibitors have not demonstrated therapeutic efficacy [41]. In addition to inhibiting the beneficial effects of NO, one possible explanation is the lack of isoform selectivity of the NOS inhibitors that have been examined to date.…”

Section: Nos Inhibitors In No-related Diseasesmentioning

confidence: 98%

Pharmacologic Manipulation of Nitric Oxide Signaling: Targeting NOS Dimerization and Protein-Protein Interactions

Paige¹,

Jaffrey²

2007

CTMC

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Nitric oxide (NO) is an endogenously-produced small molecule that has critical roles in cellular signaling and a variety of physiological processes in many tissues, including the brain, the vasculature, and the immune system. In several medical disorders, NO has been implicated in disease pathology, in most cases due to persistent activation or overproduction of one of three NO synthase (NOS) isoforms. Although NOS inhibitors that are both potent and cell-permeable have been developed, none is currently used in the treatment of any disorder. One reason that NOS inhibitors fail to have therapeutic efficacy may be linked to their very low isoform-selectivity. An additional possibility is that NOS inhibitors, even if they exhibit isoform selectivity, might indiscriminately affect beneficial and pathological NO signaling pathways. In this review, we discuss emerging approaches in the development of isoform-specific NOS-directed therapeutics including dimerization inhibitors, novel L-arginine (L-Arg) binding site inhibitors, and dimer stabilization. Additionally, we suggest novel strategies for the future including targeting subcellular localization of NOS and protein-protein interactions with NOS effectors.

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N??-NITRO-l-ARGININE METHYL ESTER EFFECTS ON NEUTROPHIL FUNCTION AND BACTERIAL CLEARANCE

Cited by 10 publications

References 38 publications

Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation

Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation

IgM‐enriched solution BT086 improves host defense capacity and energy store preservation in a rabbit model of endotoxemia

Pharmacologic Manipulation of Nitric Oxide Signaling: Targeting NOS Dimerization and Protein-Protein Interactions

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