Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A major determinant of survival in patients with advanced viral or bacterial infection, or following severe trauma or burns complicated by multiple organ failure, is the combination of clinical signs termed the systemic inflammatory response syndrome (SIRS). SIRS is characterized by hypotension, tachypnea, hypo- or hyperthermia and leukocytosis as well as other clinical signs and symptoms, including a depression in myocardial contractile function. Heart failure complicating systemic sepsis or other causes of SIRS is usually not accompanied by coronary artery ischemia due to hypotension, myocardial necrosis, or marked cardiac interstitial inflammatory infiltrates, and thus the cause of cardiac contractile dysfunction in this syndrome has remained unclear. However, recent evidence has implicated an endogenous nitric oxide (NO) signalling pathway within cardiac myocytes and other cellular constituents of cardiac muscle, including the microvascular endothelium, as a possible contributor to the pathogenesis of heart failure in this syndrome. Cardiac myocytes are now known to express both constitutive NO synthase (cNOS) and inducible NO synthase (iNOS) activities. Activation of cNOS appears to modulate cardiac myocyte responsiveness to muscarinic cholinergic and beta-adrenergic receptor stimulation. Induction of iNOS by soluble inflammatory mediators, including cytokines, causes a marked depression in myocyte contractile responsiveness to beta-adrenergic agonists. Thus, inappropriate activation of cNOS or excessive or prolonged induction of iNOS in the myocardium may contribute to cardiac dysfunction complicating SIRS.
J Mol Cell Cardiol 1995 Jan
PMID:Myocardial contractile dysfunction in the systemic inflammatory response syndrome: role of a cytokine-inducible nitric oxide synthase in cardiac myocytes. 753 82

Products of inducible nitric oxide synthase (iNOS) are known to be involved in lung injury following intrapulmonary deposition of immunoglobulin G immune complexes (IgG-ICx). In the current studies rat alveolar macrophages stimulated in vitro with murine interferon gamma (IFN-gamma), tumor necrosis factor alpha, interleukin 1 alpha, (IL-1 alpha), lipopolysaccharide (LPS), or IgG-ICx immunostained for iNOS and produced nitrite/nitrate- (NO2-/NO3-) in a dose- and time-dependent manner requiring availability of L-arginine. Under the same conditions, IL-4 and IL-10 reduced NO2-/NO3- generation. Type II alveolar epithelial cells, which were obtained from normal rat lungs and stimulated in vitro with IgG-ICx, LPS, or IFN-gamma, also immunostained for iNOS and generated NO2-/NO3-. Special techniques of bronchoalveolar lavage (BAL) were used to retrieve alveolar macrophages and type II alveolar epithelial cells. Under these conditions, intrapulmonary deposition of LPS yielded BAL fluids containing increased amounts of NO2-/NO3- and macrophages that spontaneously released NO2-/NO3- and stained for iNOS. After intrapulmonary deposition of IgG both macrophages as well as type II cells (retrieved by BAL) spontaneously produced NO2-/NO3- and both cell types immunostained for iNOS (approximately 20% of all type II cells and 35% of all alveolar macrophages). Using dual fluorescence staining for cell identification, frozen sections of lung tissue after IgG immune complex deposition revealed iNOS in both alveolar macrophages and type II cells. Finally, in the immune complex model of alveolitis, the appearance of iNOS in macrophages as well as macrophage production in vitro of NO2-/NO3- was dependent on the in vivo availability of tumor necrosis factor alpha, IL-1, and IFN-gamma. These studies suggest a dual cell source for nitric oxide in inflamed lungs and the requirements for iNOS of several cytokines.
Am J Respir Cell Mol Biol 1995 Jun
PMID:Lung sources and cytokine requirements for in vivo expression of inducible nitric oxide synthase. 753 74

Nitric oxide (NO) modulates the activity of a number of cell types, but little is known about its possible role in bone metabolism. In the present study we demonstrate that freshly isolated murine osteoblasts and an osteoblastic cell line express NO-synthase mRNA and release NO when stimulated with IL-1 or LPS, thus confirming the results of some recent reports using human and rat osteoblast-like cells. Synergistic effects were found between IL-1 and LPS or TNF. Enzyme induction was blocked by dexamethasone and IL-4. 1,25-dihydroxyvitamin D3 did not modify basal NO synthesis, but it markedly increased the cytokine-induced NO release. M-CSF, GM-CSF, IL-3, LIF, PTH, estradiol and calcitonin did not show significant effects on NO synthesis. NOS induction was blocked by various tyrosine-kinase inhibitors, geldanamycin and herbimycin A being the most potent. These results suggest that endogenous NO might participate in the regulation of bone remodeling at the local level, and may mediate some effects of vitamin D on bone. NO has recently been reported to inhibit osteoclastic bone resorption. The release of NO induced by bone-stimulating factors such as IL-1 may represent a protective mechanism helping to avoid excess resorption and preserve bone integrity in inflammatory conditions.
Mol Cell Endocrinol 1995 Jan
PMID:Mechanisms controlling nitric oxide synthesis in osteoblasts. 754 Sep 93

We investigated the effect of intratracheal (i.t.) lipopolysaccharide (LPS) on alveolar macrophage release of nitric oxide. Mice received i.t. LPS at doses ranging from 1 to 100 micrograms/100 g body weight and were killed at serial intervals for bronchoalveolar lavage. Control mice received i.t. phosphate-buffered saline. We found that after i.t. LPS, there was an early (1 to 3 days) influx of neutrophils followed by a later (5 to 7 days) influx of macrophages into the lungs. Alveolar macrophages lavaged from mice given i.t. LPS did not spontaneously release nitric oxide (measured as nitrite), but the capacity of these cells to release nitric oxide in vitro in response to interferon-gamma (IFN-gamma) or LPS was markedly upregulated. Alveolar macrophages lavaged from mice given i.t. LPS but not i.t. phosphate-buffered saline also expressed mRNA for inducible nitric oxide synthase as measured by semiquantitative reverse-transcription polymerase chain reaction. To investigate possible mechanisms for cellular priming for increased nitric oxide release after i.t. LPS, mice were depleted of CD4+ lymphocytes with an anti-CD4 antibody. Alveolar macrophages from CD4-depleted mice given i.t. LPS released significantly less nitric oxide in vitro in comparison to macrophages from nondepleted mice. Additional mice were treated with neutralizing doses of anti-tumor necrosis factor or anti-IFN-gamma antibody before i.t. LPS. Pretreatment with each cytokine antibody decreased but did not eliminate macrophage priming for nitric oxide release after i.t. LPS. We conclude that intratracheal LPS induces mRNA for nitric oxide synthase in alveolar macrophages, priming the cells for increased release of nitric oxide in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1995 Jul
PMID:Regulation of nitric oxide release by macrophages after intratracheal lipopolysaccharide. 754 Dec 22

Acute inhalation of toxic doses of ozone (O3) induces macrophage accumulation in the lung and the release of cytotoxic and proinflammatory mediators. To evaluate the role of macrophages and their mediators in the pathophysiologic response of the lung to O3, we examined the effects of the macrophage inhibitor, gadolinium chloride (GdCl3), on O3-induced inflammation, mediator production, and lavage fluid protein levels. Rats were pretreated with GdCl3 (7 mg/kg, intravenously) or control 24 h prior to exposure to air or O3 (2 parts per million, 3 h). Animals were killed 48 h after exposure. GdCl3 pretreatment of rats was found to abrogate O3-induced increases in the number of cells, as well as the amount of protein recovered in bronchoalveolar lavage fluid. Following GdCl3 pretreatment of rats, lung lavage cells consisting of > 90% macrophages were found to produce significantly less nitric oxide and express less inducible nitric oxide synthase (iNOS) when compared to cells from rats exposed to O3. O3-induced alterations in superoxide anion production by alveolar macrophages, both in vitro and in situ, were also attenuated by GdCl3 pretreatment of rats. In addition, increases in tumor necrosis factor alpha (TNF-alpha) and fibronectin in lung tissue induced by O3 were reduced. Taken together, these data provide support for the hypothesis that macrophages contribute to the pathogenesis of O3-induced lung injury.
Am J Respir Cell Mol Biol 1995 Aug
PMID:Inhibition of macrophages with gadolinium chloride abrogates ozone-induced pulmonary injury and inflammatory mediator production. 754 94

Prolonged hypoxia in the adult rat causes a decline in endothelium-derived nitric oxide (NO) production in the pulmonary circulation. To evaluate whether this is related to a decrease in endothelial NO synthase (NOS-III) expression, we determined the effects of hypobaric hypoxia (7 or 21 days) on NOS-III gene expression in adult rat lung. Neuronal NOS (NOS-I) expression was also examined; NOS-I has been immunohistochemically localized to rat bronchiolar epithelium. NOS-III and NOS-I mRNA abundance were assessed in reverse transcription-polymerase chain reaction assays and the proteins were evaluated by immunoblot analysis. After 7 and 21 days of hypoxia, there were increases in the steady-state levels of both NOS-III and NOS-I mRNA, rising 2.7- to 3.0-fold and 2.5- to 2.8-fold, respectively. These findings were confirmed by Northern analyses. In parallel, NOS-III and NOS-I protein abundance were also increased with hypoxia by 3.0- to 3.5-fold and 2.4- to 3.0-fold, respectively. NOS activity detected by [3H]arginine to [3H]citrulline conversion rose 109%. Thus, prolonged in vivo hypoxia causes enhancement of NOS-III and NOS-I gene expression in adult rat lung, indicating that the pulmonary expression of these genes is modulated in vivo. The increase in NOS-III expression does not explain the declines in pulmonary endothelial NO production previously observed following prolonged hypoxia in this model. Alternatively, the fall in NO production may be related to diminished NOS co-factor availability.
Am J Respir Cell Mol Biol 1995 Aug
PMID:Prolonged in vivo hypoxia enhances nitric oxide synthase type I and type III gene expression in adult rat lung. 754 96

In brain and other tissues, nitric oxide (NO) operates as a diffusible second messenger that stimulates the soluble form of the guanylyl cylase enzyme and so elicits an accumulation of cGMP in target cells. Inhibitors of NO synthesis have been used to implicate NO in a wide spectrum of physiological and pathophysiological mechanisms in the nervous system and elsewhere. The function of cGMP in most tissues, however, has remained obscure. We have now identified a compound, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), that potently and selectively inhibits NO-stimulated guanylyl cyclase activity. In incubated slices of cerebellum, ODQ reversibly inhibited the NO-dependent cGMP response to glutamate receptor agonists (IC50 approximately nM) but did not affect NO synthase activity. The compound did not affect synaptic glutamate receptor function, as assessed in hippocampal slices, nor did it chemically inactivate NO. ODQ did, however, potentially inhibit cGMP generation in response to NO-donating compounds. An action on NO-stimulated soluble guanylyl cyclase was confirmed in studies with the purified enzyme. ODQ failed to inhibit NO-mediated macrophage toxicity, a phenomenon that is unrelated to cGMP, nor did it affect the activity of particulate guanylyl cyclase or adenylyl cyclase. ODQ is the first inhibitor that acts selectively at the level of a physiological NO "receptor" and, as such, it is likely to prove useful for investigating the function of the cGMP pathway in NO signal transduction.
Mol Pharmacol 1995 Aug
PMID:Potent and selective inhibition of nitric oxide-sensitive guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. 754 33

The role of sulfhydryl groups (SH) and disulfide bonds as well as disulfide oxidoreductases in regulation of the catalytic activity of the membrane-bound constitutive isoform of nitric oxide (NO) synthase from porcine pulmonary artery endothelial cells (PAEC) was examined. Treatment of intact PAEC or a total membrane preparation isolated from PAEC with the SH alkylating agent N-ethylmaleimide (NEM) (10 to 50 microM) or with the intramolecular disulfide-forming agent diamide (20 to 100 microM) resulted in the reduction of NO synthase activity in a dose-dependent fashion. Similar loss of enzyme activity was observed when purified NO synthase from the membrane fraction of PAEC was incubated in the presence of NEM. The loss of membrane protein SH content from NEM- and diamide-treated preparations was associated with loss of NO synthase activity. In contrast, when intact PAEC or isolated total membranes derived from PAEC were treated with increasing concentrations (1 to 5 mM) of the disulfide-reducing agent dithiothreitol (DTT), but not oxidized DTT, NO synthase activity was increased by 20 to 85%. DTT reduction of native disulfides from NEM-treated preparations or of disulfides formed after diamide treatment of membranes reversed the inhibition of NO synthase activity. Similarly, enzymatic reduction by thioredoxin/thioredoxin reductase, but not by glutaredoxin, reversed the inhibition of membrane fraction and purified NO synthase isolated from diamide-treated cells. This enzyme-catalyzed disulfide reduction was > 1,000-fold more efficient than the DTT-induced reduction.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1995 Sep
PMID:Sulfhydryl-disulfide modulation and the role of disulfide oxidoreductases in regulation of the catalytic activity of nitric oxide synthase in pulmonary artery endothelial cells. 754 97

Nitric oxide (NO) has been demonstrated to play a protective role in cell injury. In this study, we have explored the effect of NO and two NO donors (sodium nitroprusside [SNP] and isosorbide dinitrate [ISDN]) on cellular glutathione (GSH) levels in a rat lung fibroblast cell line (RFL6 cells). SNP and ISDN significantly increased cellular GSH in RFL6 cells (5 x 10(-4) M SNP: 21.9 +/- 3.6 nmol/10(6) cells and 5 x 10(-3) M ISDN: 27.6 +/- 1.7 nmol/10(6) cells versus control: 13.2 +/- 0.4 nmol/10(6) cells; P < 0.05). The stimulatory effect of SNP and ISDN on GSH was first seen at 6 h and peaked at 12 to 24 h. A similar increase in GSH was observed in RFL6 cells exposed to 400 ppm NO for 7.5 h (NO: 20.5 +/- 3.4 nmol/10(6) cells versus control: 11.9 +/- 2.4; P < 0.05). SNP and ISDN also increased cellular GSH in bovine pulmonary artery smooth muscle cells (BPSMC) and bovine pulmonary artery endothelial cells (BPAEC). Buthionine sulfoximine (BSO) (0.01 mM), an inhibitor of the GSH synthetic enzyme gamma-glutamyl cysteine synthetase, blocked the increase in GSH in RFL6 cells seen with both SNP and ISDN. In BPAEC, exposure to NO donors for 24 h stimulated glutamate uptake (SNP: 441 +/- 19 pmol/10 min/10(6) cells and ISDN: 677 +/- 48 pmol/10 min/10(6) min/10(6) cells versus control: 222 +/- 9 pmol/10 min/10(6); P < 0.05). This effect paralleled the increase in GSH. In RFL6 cells, only SNP increased glutamate uptake after 24 h of incubation. In summary, NO and NO donors increase cellular GSH in RFL6 cells, BPAEC, and BPSMC. The mechanism of this effect is unclear but may involve upregulation of the normal GSH synthetic pathways. This observation may explain in part the protective effect of NO seen in some cell culture systems and may contribute to a protective effect against oxidant injury in vivo.
Am J Respir Cell Mol Biol 1995 Oct
PMID:Nitric oxide increases cellular glutathione levels in rat lung fibroblasts. 754 74

The distribution of the enzyme synthesizing nitric oxide (NO) has been characterized in several mammalian enteric nervous systems. Two methods, immunohistochemical staining, employing anti-nitric oxide synthase antibodies, and histochemical localization of NADPH-diaphorase (NADPH-D), have given the same results. On the other hand, few studies have investigated nitric oxide synthase (NOS) in the gastrointestinal mucosa. Our study demonstrated the presence and distribution of the enzyme, NADPH-D, throughout all layers of the neonatal piglet intestinal tract. In the neonatal piglet, NADPH-D activity was found in nerve fibers parallel to the circular and to the longitudinal muscles and in the ganglion cells of Auerbach's plexus. However, the majority of NADPH-D activity was localized to the mucosa. Furthermore, the most intense activity in the mucosa was observed in villous epithelial cells. Other mucosal cells which were NADPH-D positive included the glandular epithelium and crypt cells. In addition, glandular epithelium in the deeper submucosa had very strong NADPH-D activity. Our results support the hypothesis that locally produced NO mediates physiological functions in the intestinal mucosa and submucosa.
Cell Mol Biol Res 1995
PMID:NADPH-diaphorase activity in piglet intestinal mucosa. 755 Apr 55


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