Role of Nitric Oxide Pathway in the Protection Against Lethal Endotoxemia Afforded by Low Doses of Lipopolysaccharide

Rojas, Armando; Padron, Jorge L.; Caveda, Luis; Palacios, Miriam; Moncada, S.

doi:10.1006/bbrc.1993.1237

Cited by 41 publications

(23 citation statements)

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“…Our finding that systemic NOx was highest in individuals tolerant of malaria parasitemia is consistent with the notion that NO plays a role in the tolerance of malaria-exposed adults, as hypothesized in children (6, 15), but does not prove it. Although NO was previously thought to play a key role in mediating the related phenomenon of endotoxin tolerance (23,58,77), a growing body of evidence suggests that other mechanisms could be more important (21). In fact, recent evidence suggests that at least in NOS2 knockout mice, NO is dispensable for the development of endotoxin tolerance (76).…”

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confidence: 99%

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Nitric Oxide Production and Mononuclear Cell Nitric Oxide Synthase Activity in Malaria-Tolerant Papuan Adults

Boutlis

Tjitra

Maniboey³

et al. 2003

Infect Immun

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Individuals living in regions of intense malaria transmission exhibit natural immunity that allows them to be without fever and other symptoms for most of the time despite frequent parasitization. Although this tolerance of parasitemia appears to be more effective in children than in adults (as evidenced by lower parasitemia fever thresholds with age), adults do exhibit a degree of tolerance but the mechanism(s) underlying this are unclear. Asymptomatic malaria-exposed children have higher levels of nitric oxide (NO) than children with severe disease, and NO has been proposed as a mediator of malarial tolerance. However, the ability of highly malaria-exposed asymptomatic adults to generate high-level basal NO is unknown, as is the relationship between NO and malaria tolerance in adults. The relationship between NO and malaria parasitemia was therefore determined in asymptomatic adults from Papua, Indonesia. Adults with Plasmodium falciparum parasitemia had markedly increased basal systemic NO production relative to aparasitemic Papuan controls, who in turn produced more NO than healthy controls from a region without malaria. Immunoglobulin E levels were universally elevated in malaria-exposed Papuan subjects, suggesting that the prevalence of intestinal parasitosis may be high and that nonmalarial infection may also contribute to high basal NO production. Basal peripheral blood mononuclear cell (PBMC) NO synthase activity was elevated in Papuans but poorly correlated with systemic NO production, suggesting that NO production in this setting arises not only from PBMCs but also from other tissue and cellular sources. NO production was associated with and may contribute to malaria tolerance in Papuan adults.The natural history of malaria in regions where it is endemic is characterized by long periods of asymptomatic parasitemia punctuated by episodic clinical attacks that decrease in frequency with age (40, 57). Although the immune processes preventing symptoms such as fever in chronically parasitized individuals are poorly understood, this aspect of immunity (malarial tolerance) is thought to be most efficient in childhood and then declines with age (18,41,70). This is because the threshold of parasitemia associated with fever appears to be age dependent and higher in children than adults from geographically diverse regions where malaria is endemic (56, 65). Nitric oxide (NO) has been proposed as the mediator of tolerance in populations in regions where malaria is endemic (15) on the basis that NO production in asymptomatic malariaexposed children exceeds that of children with severe malaria (1, 5) and that parallels exist between the malaria tolerant state and endotoxin tolerance (72). Indeed, in 1965 it was shown that cross-tolerance to bacterial lipopolysaccharide could be induced by experimentally infecting prisoners with Plasmodium vivax (61); this finding is in accord with present molecular models of tolerance (21). Downregulation of the endogenous pyrogen tumor necrosis factor alpha (TNF-␣) and upregulation...

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Section: Downloaded Frommentioning

confidence: 99%

“…Downregulation of the endogenous pyrogen tumor necrosis factor alpha (TNF-␣) and upregulation of NO are thought to be typical manifestations of endotoxin tolerance in mononuclear cells (72). In addition, NO is thought to play a key role in tolerance induction (23,58,77). This latter role of NO is the basis on which the above hypothesis was formulated (15).…”

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confidence: 99%

Nitric Oxide Production and Mononuclear Cell Nitric Oxide Synthase Activity in Malaria-Tolerant Papuan Adults

Boutlis

Tjitra

Maniboey³

et al. 2003

Infect Immun

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“…However, the published literature is conflicting in this regard with studies reporting both increases [26,27,30] and decreases [28,29] in TNF-· production following NOS inhibition with arginine-derived compounds such as L-NA, L-NAME and N G -monomethyl-L-arginine. As pro-inflammatory cytokines are mediators of LPS-induced sickness behaviour, we examined the effect of L-NA on the production of the pro-inflammatory cytokines IL-1ß, IL-6 and TNF-· following an in vivo LPS challenge.…”

Section: Discussionmentioning

confidence: 78%

“…Previous reports indicate that NO has an inhibitory feedback effect on the production of the pro-inflammatory cytokines TNF-· [26,27] and IL-6 [29]. However, the published literature is conflicting in this regard with studies reporting both increases [26,27,30] and decreases [28,29] in TNF-· production following NOS inhibition with arginine-derived compounds such as L-NA, L-NAME and N G -monomethyl-L-arginine.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Constitutive Nitric Oxide Production Increases the Severity of Lipopolysaccharide-Induced Sickness Behaviour: A Role for TNF-α

Connor¹,

O'Sullivan²,

Nolan³

et al. 2002

Neuroimmunomodulation

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Administration of bacterial lipopolysaccharide (LPS) to rodents induces hypophagia, body weight loss and hypolocomotion, a constellation of symptoms collectively referred to as ‘sickness behaviour’. We examined the role of the gaseous transmitter nitric oxide (NO) in mediating LPS-induced sickness behaviour in rats. Treatment with the non-selective NO synthase (NOS) inhibitor N^G-nitro-L-arginine (L-NA) (20 mg/kg; i.p.) increased the severity of LPS-induced sickness behaviour in rats, suggesting that endogenous NO does not act as a mediator of LPS-induced sickness behaviour, but may rather have a protective role, acting in an inhibitory feedback manner to limit LPS-induced sickness. To evaluate the role of the different NOS isoforms in this response, we examined the effect of the neuronal NOS inhibitor, 7-nitroindazole (7-NI; 25 and 50 mg/kg; i.p.), and the inducible NOS inhibitor, aminoguanidine (AGN; 50 and 100 mg/kg; i.p.). Neither 7-NI nor AGN significantly altered LPS-induced sickness behaviour. Therefore, it is likely that the endothelial isoform of NOS mediates the effect of L-NA on LPS-induced sickness behaviour. As pro-inflammatory cytokines are mediators of LPS-induced sickness behaviour, we examined the effect of L-NA (20 mg/kg; i.p.) on LPS-induced interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α production. L-NA increased LPS-induced TNF-α without significantly altering IL-1β or IL-6 production. Moreover, pre-treatment with the TNF-α inhibitor pentoxyfilline (25 mg/kg; i.p.) largely reversed the augmenting effect of L-NA on LPS-induced sickness behaviour, suggesting that the ability of L-NA to increase TNF-α production underpinned its ability to increase the severity of sickness. In conclusion, L-NA increases the severity of LPS-induced sickness behaviour, most likely by blocking the tonic inhibitory action of constitutively produced NO on TNF-α production.

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“…Accumulated evidence has shown that lipopolysaccharide (LPS) and/or cytokines induce the production of a large amount of nitric oxide (NO) to protect against infection (1,2), although the over-produced NO has a common cause with fatal damage to organs (3,4). The synthesis of tetrahydrobiopterin (BH4), which is a cofactor for NO synthase (NOS), is also induced along with the expression of inducible NOS (iNOS) by LPS and/or cytokines (5,6).…”

Section: Introductionmentioning

confidence: 99%

Stimulation of Tetrahydrobiopterin Synthesis by Cyclosporin A during Lipopolysaccharide Treatment in Vascular Endothelial Cells

et al. 2002

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We examined the effect of immunosuppressant cyclosporin A (CsA) on the synthesis of tetrahydrobiopterin (BH4), which is a cofactor for nitric oxide synthase (NOS), during treatment with lipopolysaccharide (LPS) in mouse brain microvascular endothelial cells. Addition of LPS to the endothelial cells increased the BH4 content and the mRNA level of GTP-cyclohydrolase I (GTPCH), the rate-limiting enzyme of BIÌ4 synthesis, and the LPSínduced increases in both the BH4 content and expression of GTPCH mRNA were further stimulated by the cotreatment with CsA. 2,4-Diamino-6-hydroxypyrimidme, an inhibitor of GTPCH, blocked the increase in BH4 content induced by CsA during the LPS treatment. Moreover. CsA stimulated the expression of inducible NOS (iNOS) mRNA during the LPS treatment. These findings suggest that CsA stimulates LPS-induced BH4 synthesis through the induction of GTPCH, and iNOS expression. CsA may increase NO production during LPS treatment in brain microvascular endothelial cells.

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Role of Nitric Oxide Pathway in the Protection Against Lethal Endotoxemia Afforded by Low Doses of Lipopolysaccharide

Cited by 41 publications

References 0 publications

Nitric Oxide Production and Mononuclear Cell Nitric Oxide Synthase Activity in Malaria-Tolerant Papuan Adults

Nitric Oxide Production and Mononuclear Cell Nitric Oxide Synthase Activity in Malaria-Tolerant Papuan Adults

Inhibition of Constitutive Nitric Oxide Production Increases the Severity of Lipopolysaccharide-Induced Sickness Behaviour: A Role for TNF-α

Stimulation of Tetrahydrobiopterin Synthesis by Cyclosporin A during Lipopolysaccharide Treatment in Vascular Endothelial Cells

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