Nitric Oxide Inhibits Numerous Features of Mast Cell–Induced Inflammation

Gaboury, Jeffrey P.; Niu, Xiao-Fei; Kubes, Paul

doi:10.1161/01.cir.93.2.318

Cited by 116 publications

(76 citation statements)

References 50 publications

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“…This observation added to existing evidence that NO is an important regulator of MC activity, modulating cell survival, mediator secretion, and gene expression (11)(12)(13)(14)(15). The ability of NO to act as a potent down-regulator of multiple MC functions suggests that it is impinging upon one or more crucial signaling pathways in the cell.…”

Section: Ast Cells (Mc)mentioning

confidence: 78%

Inhibition of Calpain Is a Component of Nitric Oxide-Induced Down-Regulation of Human Mast Cell Adhesion

Forsythe

Befus

2003

The Journal of Immunology

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Nitric oxide is an important messenger that regulates mast cell activity by modifications to gene expression and intracellular pathways associated with exocytosis and adhesion. Integrin interactions with extracellular matrix components modulate an array of cell activities, including mediator production and secretion. To investigate the molecular mechanisms underlying NO regulation of mast cell function, we studied its effects on adhesion of a human mast cell line (HMC-1) to fibronectin (FN). The NO donors S-nitrosoglutathione and S-nitroso-N-acetylpenicillamine strongly down-regulated the adhesion of HMC-1 to FN. Inhibitors of soluble guanylate cyclase and protein kinase G did not alter the response of cells to NO. A peroxynitrite scavenger did not affect modulation of adhesion by NO, nor could the effect of NO be mimicked by the peroxynitrite-producing compound 3-morpholinosydnonimine. NO donors inhibited the cysteine protease, calpain, while calpain inhibitors mimicked the effect of NO and led to a decrease in the ability of HMC-1 cells to adhere to FN. Thus, NO is an effective down-regulator of human mast cell adhesion. The mechanism for this action does not involve peroxynitrite or activation of soluble guanylate cyclase. Instead, a portion of NO-induced down-regulation of adhesion may be attributed to inhibition of the cysteine protease, calpain, an enzyme that has been associated with control of integrin activation in other cell types. The inhibition of calpain is most likely mediated via nitrosylation of its active site thiol group. Calpain may represent a novel therapeutic target for the regulation of mast cell activity in inflammatory disorders.

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Section: Ast Cells (Mc)mentioning

confidence: 78%

Inhibition of Calpain Is a Component of Nitric Oxide-Induced Down-Regulation of Human Mast Cell Adhesion

Forsythe

Befus

2003

The Journal of Immunology

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“…One possibility is that NO interacts directly with the haeme prosthetic group within NADPH oxidase to inhibit superoxide production (Fukahori et al, 1994;Wang et al, 1995) thereby reducing tissue damage associated with production of this free radical (Vega et al, 1998). Elevated levels of superoxide radicals produce mediator release from mast cells (Mannaioni et al, 1991), whereas NO has an important stabilising eect on this cell type (Gaboury et al, 1996). In addition, raised levels of superoxide activate NF-kB (Sen & Packer, 1996) whereas NO prevents activation of this transcription factor.…”

Section: Discussionmentioning

confidence: 99%

21‐NO‐prednisolone is a novel nitric oxide‐releasing derivative of prednisolone with enhanced anti‐inflammatory properties

Paul-Clark

Soldato²,

Fiorucci

et al. 2000

British J Pharmacology

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1 Anti-in¯ammatory eects of a novel derivative of the glucocorticoid prednisolone were investigated. NCX-1015 (prednisolone 21-[(4'-nitrooxymethyl)benzoate]) incubation in human platelet-rich plasma produced a time (0 ± 60 min) and concentration (3 ± 300 mM) dependent release of nitrite, that was mirrored by accumulation of cyclic guanosine monophosphate in the human platelets. Intraperitoneal injection of NCX-1015 to mice (up to 27.7 mmol kg 71) produced nitrite accumulation in the peritoneal cavity maximal at 60 min. 2 NCX-1015 dose-dependently induced the steroid sensitive cell surface marker CD163 in human peripheral blood mononuclear cells (PBMCs). NCX-1015 was more potent than prednisolone in inducing CD163. Similarly, lipopolysaccharide induced interleukin-1b release from these cells was inhibited by NCX-1015 with higher potency than prednisolone. 3 In the zymosan peritonitis model, NCX-1015 was more active than prednisolone in suppressing neutrophil extravasation (ED 50 of 5.5 and 25.8 mmol kg 71, respectively), nitrite accumulation (ED 50 of 1.38 and 22.2 mmol kg 71, respectively) and release of the chemokine KC (ED 50 of 5.5 and 27.7 mmol kg 71, respectively) as determined at the 4 h time-point. No dierences were measured for the levels of interleukin-1b or prostaglandin E 2 . NCX-1015 administered orally was also found to be equally active. Co-administration of the nitric oxide donors NOC-18 ((z)-1-[(2-aminoethyl)-N-(2-aminoethyl)amino] diazen-1-ium-1, 2-diolate; 7.9 mmol kg 71 ) or sodium nitroprusside (13.8 mmol kg 71) with prednisolone resulted in an additive anti-migratory action. 4 In a chronic model of granulomatous tissue in¯ammation, administration of NCX-1015 (13.9 mmol kg 71 ) from day 1 (i.e. after induction of in¯ammation) was more eective than prednisolone in reducing the granuloma dry weight, and this was associated to a lower antiangiogenic eect. 5 In conclusion we show that NCX-1015 is more potent than prednisolone in controlling several, though not all, parameters of acute and chronic in¯ammation, and propose that this eect may be due to a co-operation between the steroid moiety and nitric oxide or related species released in biological¯uids. Whereas this aspect needs to be further clari®ed, we propose NCX-1015 as the ®rst member of a novel class of anti-in¯ammatory compounds, the nitro-steroids.

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“…Using intravital microscopy, NOS inhibition with L-NAME causes a rapid increase in leukocyte adhesion within the mesenteric microcirculation. 32,33 In vitro, L-NAME exhibits a similar effect on adhesion of leukocytes to the endothelium, although only in the presence of mast cells. 32 Inhibition of NO results in oxidant release, which appears to contribute to the mast cell-induced leukocyte adhesion.…”

Section: Control Of Vascular Tone In the Mesenteric Portal And Systmentioning

confidence: 99%

“…32 Inhibition of NO results in oxidant release, which appears to contribute to the mast cell-induced leukocyte adhesion. 33 Studies with NO donors also suggest a role for NO in mediating leukocyte adhesion under conditions of oxidative stress and mast cell degranulation. 34,35 Conducted Vasodilation in the Microcirculation.…”

Section: Control Of Vascular Tone In the Mesenteric Portal And Systmentioning

confidence: 99%

The hepatic circulation in health and disease: Report of a single-topic symposium

et al. 1998

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Nitric Oxide Inhibits Numerous Features of Mast Cell–Induced Inflammation

Cited by 116 publications

References 50 publications

Inhibition of Calpain Is a Component of Nitric Oxide-Induced Down-Regulation of Human Mast Cell Adhesion

Inhibition of Calpain Is a Component of Nitric Oxide-Induced Down-Regulation of Human Mast Cell Adhesion

21‐NO‐prednisolone is a novel nitric oxide‐releasing derivative of prednisolone with enhanced anti‐inflammatory properties

The hepatic circulation in health and disease: Report of a single-topic symposium

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