Room F, 10/17/2000 9: 00 AM - 11: 00 AM (PS) Role of Transcription Factors in the Upregulation of Nitric Oxide Production in Alveolar Macrophages Following Hyperoxia In Vitro

Fluorides, being hazardous contaminants of soil and drinking water, can get in excessive amounts into human and animal bodies. This is especially true for regions where the fluoride content in soils is very high, for example, Poltava, Dnipropetrovsk, and Kirovohrad regions in Ukraine. Excessive fluoride intake can change the rate of nitric oxide production. The impact of fluorides on changes in nitric oxide production and metabolism in the heart and the role of redox-sensitive transcription factors in these changes are poorly understood. The aim of this study was to determine the effect of activation of κB transcription factors and activator protein 1 on the activity of inducible NO-synthase, constitutive isoforms of NO-synthase, nitrite and nitrate reductase, arginase, concentration of nitrites, peroxynitrite and nitrosothiols in the heart of rats during chronic fluoride intoxication. Materials and methods. The study was performed on 24 adult male Wistar rats weighing 220-260 grams. Animals were randomly divided into 4 groups of 6 animals in each (control, chronic fluoride intoxication group, κB blockade group and activator protein 1 blockade group). The experiment lasted 30 days. We determined the activity of inducible NO-synthase, constitutive isoforms of NO-synthase, the concentration of peroxynitrite alkali and alkaline earth metals, the concentration of nitrites and nitrosothiols, the activity of nitrite reductase, nitrate reductase and arginase. Results. Chronic fluoride intoxication increases the activity of inducible NO-synthase by 1.74 times, does not affect the activity of constitutive isoforms and reduces the activity of arginase by 35.68% compared with the control group of animals. The concentration of nitrites in the heart of rats increases 1.73 times, peroxynitrite 1.43 times, and the concentration of nitrosothiols doubled. The use of κB transcription factor blockers and activator protein 1 reduces nitric oxide production from NO synthases and reduces the concentrations of all nitric oxide metabolites in the heart of rats under conditions of chronic fluoride intoxication. Conclusions. Activation of κB transcription factors and activator protein 1 during chronic excessive intake of fluoride leads to hyperproduction of nitric oxide in the heart of rats due to increased activity of inducible NO-synthase and nitrite reductases. Excess production of nitric oxide under chronic fluoride intoxication leads to the accumulation of nitrites, peroxynitrite and nitrosothiols in the heart of rats.

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Mechanisms of Asbestos-induced Nitric Oxide Production by Rat Alveolar Macrophages in Inhalation and in vitro Models 11Supported by grants from NHLBI (RO1 HL39469) and NIEHS (RO1 03878).

Free Radical Biology and Medicine ◽

10.1016/s0891-5849(97)00357-2 ◽

1998 ◽

Vol 24 (5) ◽

pp. 778-788 ◽

Cited By ~ 52

Author(s):

Timothy R Quinlan ◽

Kelly A BeruBe ◽

Miles P Hacker ◽

Douglas J Taatjes ◽

Cynthia R Timblin ◽

...

Keyword(s):

Nitric Oxide ◽

Alveolar Macrophages ◽

In Vitro Models ◽

Nitric Oxide Production ◽

Oxide Production

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[52] In vitro system to study role of blood flow on nitric oxide production and cell signaling in endothelial cells

Methods in Enzymology - Nitric Oxide Part C: Biological and Antioxidant Activities ◽

10.1016/s0076-6879(99)01114-3 ◽

1999 ◽

pp. 513-522 ◽

Cited By ~ 1

Author(s):

Young-Mi Go ◽

Heonyong Park ◽

Matthew C. Maland ◽

Hanjoong Jo

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Blood Flow ◽

Cell Signaling ◽

Nitric Oxide Production ◽

In Vitro System ◽

Oxide Production

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Nitric oxide production, alveolar macrophages and type II alveolar epithelial cells in response to LPS in vivo and in vitro

Biochemical Society Transactions ◽

10.1042/bst023233s ◽

1995 ◽

Vol 23 (2) ◽

pp. 233S-233S ◽

Cited By ~ 2

Author(s):

Xiaoyang Li ◽

Kenneth Donaldson ◽

William MacNee

Keyword(s):

Nitric Oxide ◽

Epithelial Cells ◽

Alveolar Macrophages ◽

Alveolar Epithelial Cells ◽

Nitric Oxide Production ◽

Type Ii ◽

Alveolar Epithelial ◽

Oxide Production

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The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-L-arginine.

Journal of Experimental Medicine ◽

10.1084/jem.179.2.651 ◽

1994 ◽

Vol 179 (2) ◽

pp. 651-660 ◽

Cited By ~ 298

Author(s):

J B Weinberg ◽

D L Granger ◽

D S Pisetsky ◽

M F Seldin ◽

M A Misukonis ◽

...

Keyword(s):

Nitric Oxide ◽

Autoimmune Disease ◽

Nitric Oxide Synthase ◽

Nitric Oxide Production ◽

Chromosome 11 ◽

Oxide Production ◽

Oxide Synthase ◽

Inducible Nos

MRL-lpr/lpr mice spontaneously develop various manifestations of autoimmunity including an inflammatory arthropathy and immune complex glomerulonephritis. This study examines the role of nitric oxide, a molecule with proinflammatory actions, in the pathogenesis of MRL-lpr/lpr autoimmune disease. MRL-lpr/lpr mice excreted more urinary nitrite/nitrate (an in vivo marker of nitric oxide production) than did mice of normal strains and MRL-(+/+) and B6-lpr/lpr congenic strains. In addition, MRL-lpr/lpr peritoneal macrophages had an enhanced capacity to produce nitric oxide in vitro as well as increased nitric oxide synthase activity, and certain tissues from MRL-lpr/lpr mice had increased expression of inducible nitric oxide synthase (NOS) mRNA and increased amounts of material immunoreactive for inducible NOS. Oral administration of NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, prevented the development of glomerulonephritis and reduced the intensity of inflammatory arthritis in MRL-lpr/lpr mice. By using interspecific backcross mice, the gene for inducible NOS (Nosi) was mapped to mouse chromosome 11. This chromosomal localization was different from those loci that we have previously demonstrated to be linked to enhanced susceptibility to renal disease in an MRL-lpr/lpr cross. However, the chromosomal location of the NOS gene was consistent with an insulin-dependent diabetes locus identified in an analysis of nonobese diabetic (NOD) mice. These results suggest that elevated nitric oxide production could be important in the pathogenesis of autoimmunity, and that treatments to block the production of nitric oxide or block its effects might be valuable therapeutically.

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