Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.5.1.19 (NOS)
 7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO.) plays a central role in the physiology of the gastrointestinal tract and its response to critical illness. Potential sources of NO. in the gut include: intrinsic intestinal tissue (mast cells, epithelium, smooth muscle, neural plexus), resident and/or infiltrating leukocytes (neutrophils, monocytes), reduction of luminal gastric nitrate, and denitrification by commensal anaerobes. The brain and endothelial isoforms of nitric oxide synthase are expressed under resting conditions, whereas inflammatory stimuli are required for the induction of the inducible type. Under resting conditions, mucosal perfusion is regulated by NO. derived from the vascular endothelium of the mesenteric bed. During inflammation, excessive NO. production from the inducible synthase may contribute to mucosal hyperemia. Coordination of peristalsis and sphincteric action is mediated by the release of NO., which acts as the principal neurotransmitter of the nonadrenergic, noncholinergic enteric nervous system. Alterations in bowel motility, such as ileus, result from excessive concentrations of NO. generated during endotoxicosis and inflammatory bowel disease. The role of NO. in the regulation of salt and water secretion is poorly understood. Endotoxin-induced inhibition of gastric acid secretion appears to be mediated by the action of NO. on parietal cells. NO. may protect the gastrointestinal mucosa from a variety of stimuli (caustic ingestion, ischemia, ischemia/reperfusion injury, early endotoxic shock) by maintaining mucosal perfusion, inhibiting neutrophil adhesion to mesenteric endothelium, blocking platelet adhesion, and preventing mast cell activation. Excessive NO., however, may directly injure the mucosa. Barrier function of the intestinal mucosa is protected by NO. in the early stages of injury, when neutrophil adhesion, ischemia, and mast cell activation are relevant. Inhibition of NO. synthesis ameliorates barrier dysfunction during more advanced stages of inflammation, when activation of inducible NOS yields toxic concentrations of NO.. At high concentrations, NO. disrupts the actin cytoskeleton, inhibits ATP formation, dilates cellular tight junctions, and produces a hyperpermeable state. Selective inhibition of the inducible isoform of NOS and maintenance of the constitutive types may be therapeutic.
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PMID:Nitric oxide in the gut. 758 76

Nitric oxide (NO.) plays a central role in the Physioliology of the gastrointestinal tract and its response to critical illness. Potential sources of NO. in the gut include: intrinsic intestinal tissue (mast cells, epithelium, smooth muscle, neural plexus), resident and/or infiltrating leukocytes (neutrophils, monocytes), reduction of luminal gastric nitrate, and denitrification by commensal anaerobes. The brain and endothelial isoforms of nitric oxide synthase are expressed under resting conditions, whereas inflammatory stimuli are required for the induction of the inducible type. Under resting conditions, mucosal perfusion is regulated by NO. derived from the vascular endothelium of the mesenteric bed. During inflammation, excessive NO. production from the inducible synthase may contribute to mucosal hyperemia. Coordination of peristalsis and sphincteric action is mediated by the release of NO., which acts as the principal neurotransmitter of the nonadrenergic, noncholinergic enteric nervous system. Alterations in bowel motility, such as ileus, result from excessive concentrations of NO. generated during endotoxicosis and inflammatory bowel disease. The role of NO. in the regulation of salt and water secretion is poorly understood. Endotoxin-induced inhibition of gastric acid secretion appears to be mediated by the action of NO. on parietal cells. NO. may protect the gastrointestinal mucosa from a variety of stimuli (caustic ingestion, ischemia, ischemia/reperfusion injury, early endotoxic shock) by maintaining mucosal perfusion, inhibiting neutrophil adhesion to mesenteric endothelium, blocking platelet adhesion, and preventing mast cell activation. Excessive NO., however, may directly injure the mucosa. Barrier function of the intestinal mucosa is protected by NO. in the early stages of injury, when neutrophil adhesion, ischemia, and mast cell activation are relevant. Inhibition of NO. synthesis ameliorates barrier dysfunction during more advanced stages of inflammation, when activation of inducible NOS yields toxic concentrations of NO.. At high concentrations, NO. disrupts the actin cytoskeleton, inhibits ATP formation, dilates cellular tight junctions, and produces a hyperpermeable state. Selective inhibition of the inducible isoform of NOS and maintenance of the constitutive types may be therapeutic.
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PMID:Nitric oxide in the gut. 770 93

There is growing evidence that endogenous nitric oxide (NO) regulates mucosal barrier integrity under physiological conditions and counters the increase in mucosal permeability associated with acute pathophysiological states. The potential mechanisms of action for the protective effects of NO are discussed. These include maintenance of blood flow, inhibition of platelet and leukocyte adhesion and/or aggregation within the vasculature, modulation of mast cell reactivity, and scavenging of reactive oxygen metabolites such as superoxide. On the basis of the data presented, we conclude that both constitutive nitric oxide synthase (cNOS)-derived endogenous NO and exogenous NO (from NO donors) appear to reduce the sequelae of acute inflammation. The second section of this review summarizes the data germane to prolonged (chronic) inflammatory conditions associated with the overproduction of NO from the inducible form of NOS (iNOS). Some emphasis is placed on the role of NO in sepsis and inflammatory bowel disease (IBD), and data to suggest that NO, or more specifically a NO-derived mediator, is involved in these disorders are summarized. These studies are compared with recent publications suggesting that inhibition of NO synthesis with nonspecific inhibitors of NOS or selective iNOS inhibitors may not protect in models of sepsis or IBD. Overall, the review highlights the potential importance of the type of NOS enzyme involved in the particular inflammatory process being studied.
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PMID:A critical role for nitric oxide in intestinal barrier function and dysfunction. 877 63

1. In healthy subjects, exhaled NO originates mainly from the upper airways with only a minor contribution from the lower airways and the lungs. A large NO production takes place in the epithelium of the paranasal sinuses and this NO contributes considerably to the levels of NO found in nasally exhaled air. Immunohistochemical and mRNA in situ hybridisation studies suggest that sinus NO synthase is identical or very closely related to the human iNOS. Furthermore, the NOS activity in sinus mucosa is mostly Ca(2+)-independent. However, the regulation of sinus NOS expression seems to differ fundamentally from what has earlier been described for iNOS. Thus, sinus NOS is constitutively expressed and seems resistant to steroids. The high local NO concentrations in the nasal airways and the sinuses may help to protect against airborne infectious agents. Thus, airborne NO may represent the very first line of defence in the airways, possibly acting on pathogens even before they reach the mucosa. 2. Nasal concentrations of NO are markedly reduced in children with Kartagener's syndrome and in patients with CF. A simple chemiluminescence test test could be of help in early non-invasive diagnosis of these chronic airway diseases. 3. Inhaled endogenous NO, derived from the upper airways, may be involved in regulation of pulmonary function in man. NO will reach the lower airways and the lungs with the inspired air and at levels that are especially high during nasal breathing. This NO may act by enhancing blood flow preferentially in well ventilated areas of the lung, thus optimizing ventilation/perfusion matching. The involvement of autogenous NO in regulation of pulmonary function may represent a novel physiological principle, namely that of an enzymatically produced airborne messenger. The term "aerocrine" may be appropriate for this action of NO in the airways. These findings may also help to explain one biological role of the enigmatic human paranasal sinuses, the major sources of NO in the upper airways. 4. A continuous production of NO takes place in the acidic stomach through chemical reduction of nitrite present in swallowed saliva. This is the first evidence of non-enzymatic NO production in humans. Stomach NO may be involved in local defence against swallowed pathogens and in regulation of superficial mucosal blood flow and mucus production. 5. Luminal concentrations of NO are increased in the lower airways of asthmatic children, in the colon of patients with inflammatory bowel disease, and in the urinary bladder of patients with cystitis. Local steroid treatment reduces orally exhaled NO levels in asthmatic children. Nasal NO levels did not differ between controls and asthmatic children with or without concomitant allergic rhinitis. In conclusion, nitric oxide found in exhaled air originates mainly in the upper airways. A large production of NO takes place in the paranasal sinuses from a constitutively-expressed, steroid-resistant "inducible-like" NO synthase in the epithelial cells. Sinus NO contributes substantially to levels of NO found in nasally exhaled air. Sinus NO may have a dual function. First, the very high concentrations in the sinuses may contribute to local host defence. Second, when diluted in the inhaled air, sinus-derived NO may act as an "aerocrine" messenger, with distal effects on pulmonary blood flow and oxygen uptake. Intubated patients are deprived of autogenous NO from the upper airways and might benefit from substitution. Measurements of local NO production in hollow organs may be done easily by analysing the concentrations of NO gas in luminal air. Such noninvasive methods may be useful not only to explore the role of NO in inflammation and host defence, but also in the diagnosis and monitoring of inflammatory mucosal diseases such as asthma, ulcerative colitis and cystitis. Thus, airborne NO may be looked upon as a marker of inflammation and as an aerocrine messenger in humans.
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PMID:Airborne nitric oxide: inflammatory marker and aerocrine messenger in man. 887 55

Inflammatory bowel disease (IBD) is characterized by altered immunoregulation and augmented intestinal synthesis of nitric oxide. The purpose of this study was to determine the effects of exogenous IL-4, introduced by a recombinant human type 5 adenovirus (Ad5) vector, on the tissue injury associated with an experimental model of colonic immune activation and inflammation. Colitis was induced in rats by the intrarectal administration of trinitrobenzene sulfonic acid (TNB) dissolved in 50% ethanol, and control rats received saline via the same route. 1 h later, all rats were randomized into two groups. The first group was injected intraperitoneally (ip) with 3.0 x 10(6) plaque forming units (PFUs) of Ad5 transfected with murine interleukin-4 (Ad5IL-4) and the second group was injected ip with the same amount of Ad5 expressing the Escherichia coli Lac Z gene (Ad5LacZ). One-half of the colitic and control rats were injected again with 3.0 x 10(6) PFUs of Ad5IL-4 or Ad5LacZ on day 3 of the 6-d study. When introduced once or twice via the peritoneal route into control rats, Ad5LacZ was localized to the serosal lining of the peritoneal cavity, the diaphragm and the liver on day 6. One or two injections of Ad5IL-4 into rats also produced measurable levels of circulating IL-4. TNB-colitis in both Ad5LacZ-treated groups was associated with pronounced elevations in serum IFN-gamma, and mucosal ulceration of the distal colon. Myeloperoxidase and inducible nitric oxide synthase II (NOS II) synthetic activity were also increased by 30- and fivefold, respectively, above control levels in the distal colon. However, two injections of Ad5IL-4 into colitic rats caused the overexpression of IL-4, and significantly inhibited tissue damage, serum and colon IFN-gamma levels and myeloperoxidase activity in the distal colon. In addition, NOS II gene expression and NOS II nitric oxide synthesis was significantly inhibited. No therapeutic effect was observed in rats injected once with Ad5IL-4. Thus, IL-4, introduced by Ad5, is therapeutic during acute inflammation in the rat colon. The therapeutic effect of IL-4 was associated with an inhibition of inducible nitric oxide expression and a reduction in nitric oxide synthesis.
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PMID:Therapeutic effects of interleukin-4 gene transfer in experimental inflammatory bowel disease. 938 41

Inflammatory bowel disease (IBD) is characterised by altered immunoregulation and augmented synthesis of nitric oxide. The purpose of this study was to determine the effects of exogenous IL-4, introduced by a recombinant human type 5 adenovirus (Ad5) vector, on the tissue injury associated with an experimental model of colonic immune activation and inflammation. Colitis was induced in rats by the intrarectal administration of trinitrobenzene sulfonic acid (TNB) dissolved in 50% ethanol, and control rats received saline via the same route. 1 h later, all rats were randomized into two groups. The first group was injected intraperitoneally (i.p.) with 3.0 x 10(6) plaque forming units (PFUs) of Ad5 transfected with murine interleukin-4 (Ad5IL-4) and the second group was injected i.p. with the same amount of Ad5 expressing the Escherichia coli Lac Z gene (Ad5LacZ). One-half of the colitic and controls rats were injected again with 3.0 x 10(6) PFUs of Ad5IL-4 or Ad5LacZ on day 3 of the 6-d study. When introduced once or twice via the peritoneal route into control rats Ad5LacZ was localised to the serosal lining of the peritoneal cavity, the diaphragm and the liver on day 6. One or two injections of Ad5IL-4 into rats also produced measurable levels of circulating IL-4. TNB-colitis in both Ad5LacZ-treated groups was associated with pronounced elevations in serum IFN-gamma, and mucosal ulceration of the distal colon. Myeloperoxidase and inducible nitric oxide synthase II (NOS II) synthetic activity were also increased by 30- and fivefold, respectively, above control levels in the distal colon. However, two injections of AD5IL-4 into colitic rats caused the overexpression of IL-4, and significantly inhibited tissue damage, serum and colon IFN-gamma levels and myeloperoxidase activity in the distal colon. In addition, NOS II gene expression and NOS II nitric oxide synthesis was significantly inhibited. No therapeutic effect was observed in rats injected once with AD5IL-4. Thus, IL-4, introduced by Ad5, is therapeutic during acute inflammation in the rat colon. The therapeutic effect of IL-4 was associated with an inhibition of inducible nitric oxide expression and a reduction in nitric oxide synthesis.
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PMID:Viral vectors expressing immunoregulatory cytokines to treat inflammatory bowel disease. 961 4

Increased nitric oxide (NO) production by inducible nitric oxide synthase (iNOS) has been associated with intestinal inflammation, including human inflammatory bowel disease. However, NO can downregulate endothelial activation and leukocyte adhesion, critical steps in the inflammatory response. Using primary cultures of human intestinal microvascular endothelial cells (HIMEC), we determined the role of NO in the regulation of HIMEC activation and interaction with leukocytes. Both nonselective (NG-monomethyl-L-arginine) and specific (N-iminoethyl-L-lysine) competitive inhibitors of iNOS significantly increased binding of leukocytes by HIMEC activated with cytokines and lipopolysaccharide. Increased adhesion was reversible with the NOS substrate L-arginine and was not observed in human umbilical vein endothelial cells (HUVEC). Activation of HIMEC significantly upregulated HIMEC iNOS expression and NO production. NOS inhibitors did not augment cell adhesion molecule levels in activated HIMEC but did result in sustained increases in intracellular reactive oxygen species. In addition, antioxidant compounds reversed the effect of NOS inhibitors on HIMEC-leukocyte interaction. Taken together, these data suggest that after HIMEC activation, iNOS-derived NO is an endogenous antioxidant, downregulating leukocyte binding and potentially downregulating intestinal inflammation.
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PMID:iNOS expression in human intestinal microvascular endothelial cells inhibits leukocyte adhesion. 972 73

Nitric oxide (NO) and reactive oxygen species (ROS) are important mediators in the pathogenesis of inflammatory bowel disease (IBD). NO in IBD can be either harmful or protective. NO can react with superoxide anions (O2.-), yielding the toxic oxidizing agent peroxynitrite (ONOO-). Peroxynitrite induces nitration of tyrosine residues (nitrotyrosine), leading to changes of protein structure and function. The aim of this study was to identify the cellular source of inducible nitric oxide synthase (iNOS) and to localize superoxide anion-producing cells in mucosal biopsies from patients with active IBD. Additional studies were performed to look at nitrotyrosine formation as a measure of peroxynitrite-mediated tissue damage. For this, antibodies against iNOS, endothelial NOS (eNOS), and nitrotyrosine were used. ROS-producing cells were detected cytochemically. Inflamed mucosa of patients with active IBD showed intense iNOS staining in the epithelial cells. iNOS could not be detected in non-inflamed mucosa of IBD patients and control subjects. eNOS was present in blood vessels, without any difference in the staining intensity between IBD patients and control subjects. ROS-producing cells were increased in the lamina propria of IBD patients; a fraction of these cells were CD15-positive. Nitrotyrosine formation was found on ROS-positive cells. These results show that iNOS is induced in epithelial cells from patients with active ulcerative colitis or Crohn's disease. Nitration of proteins was detected only on the ROS-producing cells at some distance from the iNOS-producing epithelial cells. These findings indicate that tissue damage during active inflammation in IBD patients is probably more related to ROS-producing cells than to NO. One may speculate that NO has a protective role when during active inflammation other mucosal defence systems are impaired.
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PMID:Expression of nitric oxide synthases and formation of nitrotyrosine and reactive oxygen species in inflammatory bowel disease. 1020 92

1. The inducible isoform of nitric oxide synthase (iNOS) may be involved in the pathogenesis of inflammatory bowel disease. Using the human intestinal epithelial cell line, Caco-2, iNOS expression, regulation and sensitivity to the glucocorticoid, dexamethasone after cytokine exposure and its relationship to the degree of differentiation has been studied. 2. NOS activity, assessed by NO2- and NO3- release, was time-dependently increased after exposure to interferon gamma alone or in combination with interleukin-1beta and tumour necrosis factor alpha. 3. Cytokine-induced iNOS activity was increased with days in culture over 20 days and number of passages, suggesting iNOS up-regulation during enterocyte-like differentiation. This activity was inhibited by the selective iNOS inhibitor 1400 W (0.1 - 100 microM). In addition, iNOS protein induction was confirmed by Western blot. 4. Actinomycin D (5 microg ml(-1) inhibited cytokine-induced iNOS activity, protein expression and mRNA level. Pyrrolidine dithiocarbamate (PDTC: 10 - 200 microM) and 3,4 dichloroisocoumarin (0.1 - 100 microM) reduced cytokine-induced iNOS activity and protein expression at both day 10 and 15 after confluence. PDTC also decreased iNOS mRNA levels, suggesting NF-kappaB involvement in its transcription at these times. 5. The tyrphostins A25 and B42 reduced cytokine-induced iNOS activity at both day 10 and 15 after confluence, indicating the JAK-2 kinase is also involved at these times. The tyrphostins also reduced the iNOS protein expression. 6. Dexamethasone (0.1 - 10 microM, for 24 h) reduced cytokine-induced iNOS activity at day 15 and 20 after cell confluence, but not at day 5 or 10. 7. Dexamethasone (5 microM) decreased cytokine-induced iNOS protein expression at day 10 as well as at day 15 after confluence. 8. These findings indicate that iNOS induction and its inhibition by dexamethasone in this human intestinal epithelial cell line is dependent on the degree of differentiation.
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PMID:Regulation of induction of nitric oxide synthase and the inhibitory actions of dexamethasone in the human intestinal epithelial cell line, Caco-2: influence of cell differentiation. 1051 52

Inflammatory disease is associated with increased production of nitric oxide (NO) and activation of the inducible nitric oxide synthase (iNOS) pathway. Several studies have addressed the role of NO as a mediator of cytokine effects on bone cell activity in vitro. Stimulatory and inhibitory actions have been found, however, depending on the concentrations produced and model system used. In view of this, it has been difficult to predict whether increased production of NO during inflammation is likely to increase bone loss or prevent it. We have investigated the pathogenic role of NO in an animal model of inflammation-induced osteoporosis (IMO). NO production was increased in IMO when compared with controls (+344%; p < 0.01), and this was accompanied by activation of inducible NOS (iNOS) in the bone marrow space. Bone mineral density (BMD) was reduced in IMO when compared with controls (-64%; p < 0.01), and this was found to be associated with reduced osteoblast numbers (-44%; p < 0.05) and increased osteoclast numbers (+38%; p < 0.01). The NOS inhibitor L-NMMA reversed the deleterious effects of IMO on bone mass and bone turnover, but L-NMMA had no effect on bone mass in control animals. This study has important implications for many inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease which are associated with increased NO production and osteoporosis. Our data not only suggest that iNOS activation and increased NO production contribute to the pathogenesis of osteoporosis in these situations, but also suggest that NOS inhibitors could be of therapeutic value in the prevention and treatment of such bone loss.
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PMID:Evidence for a pathogenic role of nitric oxide in inflammation-induced osteoporosis. 1062 73


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