Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluated regional blood flows in a hyperdynamic sepsis model and the reversal of increased flows by blockade of nitric oxide (NO) synthase. Seven awake sheep were continuously infused with Escherichia coli endotoxin [lipopolysaccharide (LPS), 10 ng.kg-1.min-1] for 48 h. The NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 25 mg/kg) was injected after 24 h. Blood flows to systemic organs were determined with the radioactive microsphere technique. LPS induced elevation of cardiac index by 36% (P < 0.05) and a fall in systemic vascular resistance index by 37% (P < 0.05) at 0 h [time of L-NAME administration, 24 h after infusion of LPS had begun] L-NAME administration normalized cardiac index [6.1 +/- 0.5 at 4 h posttreatment, 6.1 +/- 0.5 l.min-1.m-2 at -24 h (baseline)] and systemic vascular resistance index (1,333 +/- 105 at 4 h posttreatment, 1,280 +/- 163 dyn.s.cm-5.m2 at -24 h) and reduced all regional blood flows to near-baseline levels for the remainder of the study period (24 h). O2 consumption was unaffected by treatment.
 ...
PMID:Increased organ blood flow in chronic endotoxemia is reversed by nitric oxide synthase inhibition. 752 59

Since early growth response-1 (Egr-1) is required for macrophage differentiation and nitric oxide (NO) is immunosuppressive, we hypothesized that NO would reduce Egr-1 expression in rat lung macrophages. The inflammatory stimuli interferon-gamma and lipopolysaccharide induced an early, transient increase in Egr-1 mRNA (> 5-fold at 2 h) and a sustained, high level of inducible NO synthase mRNA (> 100-fold from 4 to 24 h). The NO metabolites nitrite and nitrate rose > 10-fold in medium from stimulated versus unstimulated cells over 24 h. Concomitant with elevated nitrogen oxides, Egr-1 mRNA levels declined to 80% below unstimulated cells at 24 h. This decline was blocked by an inhibitor of NO production, NG-monomethyl-L-arginine. Further, the NO donor S-nitroso-N-acetylpenicillamine inhibited Egr-1 expression in a dose-dependent manner, producing complete inhibition at 0.5 mM. The effect of S-nitroso-N-acetylpenicillamine was not due to reduced macrophage viability. We conclude that Egr-1 induction precedes inducible NO synthase induction in stimulated rat macrophages and that subsequent NO production reduces macrophage expression of Egr-1. We propose that this mechanism is used to regulate macrophage differentiation in human immunodeficiency virus infection and other inflammatory states.
 ...
PMID:Nitric oxide reduces early growth response-1 gene expression in rat lung macrophages treated with interferon-gamma and lipopolysaccharide. 752 82

Histochemical activity and immunoreactivity of nitric oxide synthase (NOS, EC 1.14.13.39) have been recently demonstrated in human lung epithelium. However, the molecular nature of NOS and the regulation and function of the enzyme(s) in the airway is not known. A549 cells (human alveolar type II epithelium-like), BEAS 2B cells (transformed human bronchial epithelial cells), and primary cultures of human bronchial epithelial cells all exhibited constitutive NOS activity that was calcium dependent and inhibitable by the NOS inhibitor NG-monomethyl-L-arginine. Nitric oxide production by epithelial cells was enhanced by culture in the presence of interferon gamma, interleukin 1 beta, tumor necrosis factor alpha, and lipopolysaccharide; the NOS activity expressed under these conditions showed less dependence on calcium, reminiscent of other inducible forms of NOS. Two distinct NOS mRNA species, homologous to previously identified constitutive brain (type I) and inducible hepatic (type II) NOS, were demonstrated by reverse transcription-polymerase chain reaction in all cell lines. Northern analysis confirmed the expression of inducible NOS mRNA. Cell culture with epidermal growth factor, a principal regulator of epithelial cell function, decreased inducible NOS activity by posttranscriptional action but did not affect constitutive NOS activity. The coexistence of constitutive and inducible NOS in human alveolar and bronchial epithelial cells is consistent with a complex mechanism evolved by epithelial cells to protect the host from microbial assault at the air/surface interface while shielding the host from the induction of airway hyperreactivity.
 ...
PMID:Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells. 752 82

Nitric oxide (NO) is a messenger molecule that is produced from L-arginine by NO synthase (NOS). Some NOS isoforms are present in cells constitutively, whereas others can be induced by cytokines. Recent evidence suggests that NO inhibits intracellular pH regulation by the vacuolar H(+)-adenosinetriphosphatase (ATPase) in macrophages, which contain an inducible form of NOS. The vacuolar H(+)-ATPase is involved in proton secretion in intercalated cells in the collecting duct. We have therefore examined the effect of NO on bafilomycin-sensitive H(+)-ATPase activity in individual cortical collecting ducts (CCD) microdissected from collagenase-treated kidneys of normal rats using a fluorometric microassay. Incubation of CCD with the NO donors, sodium nitroprusside (0.1 and 1 mM) or 3-morpholino-sydnonimine hydrochloride (SIN-1, 30 microM), caused a dose-dependent decrease in H(+)-ATPase activity. Incubation of CCD with lipopolysaccharide (LPS) and interferon-gamma, which induces NOS in macrophages, decreased H(+)-ATPase activity by 85%. This effect was prevented by simultaneous incubation with N omega-nitro-L-arginine, a competitive inhibitor of NOS, indicating that the decrease in H(+)-ATPase activity was caused by NO production. Incubation with 8-bromo-guanosine 3',5'-cyclic monophosphate (cGMP) also inhibited H(+)-ATPase activity, suggesting that NO may exert its effect in the CCD via activation of guanylyl cyclase and production of cGMP. Immunohistochemistry using antibodies to the macrophage-type NOS revealed strong labeling of intercalated cells in the CCD, confirming the presence of NOS in these cells.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Nitric oxide inhibits bafilomycin-sensitive H(+)-ATPase activity in rat cortical collecting duct. 752 55

Formation of nitrites/nitrates caused by lipopolysaccharide (LPS) in J774.2 macrophages was inhibited by thaliporphine, an aporphine derivative isolated from the plant Neolitsea konishii K. This inhibition of nitrite synthesis in LPS-stimulated macrophages by thaliporphine was similar to that by cycloheximide, NG-methyl-L-arginine (MeArg) and dexamethasone. Thaliporphine, but not MeArg, inhibited expression of inducible NO synthase without directly affecting enzyme activity. However, thaliporphine did not inhibit nitrite production by NO synthase that had already been induced by prior exposure to LPS for which any possible further induction was inhibited by cycloheximide. In endothelial cells, nitrite formation induced by bradykinin (in the presence of 0.2 mM Ca2+) was inhibited by MeArg. However, incubation of endothelial cells with dexamethasone, cycloheximide and thaliporphine did not affect this Ca(2+)-dependent nitrite production. Thaliporphine (0.1-100 microM) dose-dependently inhibited nitrite accumulation in macrophages stimulated by interleukin-1 beta (IL-1 beta) whereas nitrite formation induced by tumour necrosis factor alpha was not inhibited. LPS-stimulated IL-1 beta synthesis in macrophages was significantly inhibited by thaliporphine, but thaliporphine had only minimal effect on LPS-stimulated IL-1 beta synthesis in endothelial cells. These results demonstrate that thaliporphine inhibits LPS induction of NO synthase expression, and that the mechanism of action of thaliporphine is via inhibition of LPS-stimulated IL-1 beta synthesis in macrophages. In anaesthetized rats subjected to LPS, pretreatment with thaliporphine partially restored the fall in mean arterial pressure and the vascular hyporeactivity to noradrenaline 3 h after LPS injection. In conclusion, thaliporphine selectively inhibited expression of inducible NO synthase, and may thus hold potential for the treatment of endotoxaemia.
 ...
PMID:Thaliporphine selectively inhibits expression of the inducible, but not the constitutive, nitric oxide synthase. 752 82

The observation that spermine inhibits the endotoxin (lipopolysaccharide; LPS) induced production of nitric oxide (NO) in macrophages has been ascribed to the conversion of SP to active metabolites by the action of enzymes, such as diamine oxidases, found, for example, in bovine sera. Inhibitory effect is also observed with the oxidised metabolite of spermine, spermine dialdehyde (SDA). Inhibition appears to be at the level of induction of the inducible isoform of NO synthase (iNOS). Here we show that the activity of endogenous aldehyde dehydrogenase present in the cells influences the degree of inhibition seen with either spermine or SDA. Most significantly, inhibition of aldehyde dehydrogenase activity greatly increases (100 fold) the ability of spermine to inhibit the production of nitrite by LPS- induced macrophages. This is presumably by preserving aldehyde metabolites of spermine and thus increasing its action on the induction of iNOS. Thus, inhibition of aldehyde dehydrogenase activity in vitro or in vivo may be a useful approach to enhance the inhibitory effect of polyamines or polyamine aldehydes on iNOS induction.
 ...
PMID:Inhibition of the induction of nitric oxide synthase by spermine is modulated by aldehyde dehydrogenase. 752 90

Nitric oxide (NO) produced by endothelial cells (EC) has been shown to exert cytotoxic activity on tumor cells. In order to analyze events involved in brain metastasis, the modulation of NO production in rat-brain-derived EC was investigated. NO release was increased by tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1 beta, lipopolysaccharide or forskolin in EC219 cells, a rat-brain-microvessel-derived EC line. Dexamethasone decreased NO release by cytokine-activated EC219 cells. Tumor cells (DHD/K12/PROb, a rat colon-carcinoma cell line) were highly adherent to EC219 cells, and adhesion was not modified by TNF-alpha plus IFN-gamma, or by dexamethasone. Addition of tumor cells or tumor-cell-conditioned medium significantly inhibited NO release induced by any of the stimuli examined, but only if added during the initial phase of endothelial-cell activation. Tumor-derived suppression of NO release was also observed in primary cultures of cerebral EC. NO synthase (NOS) activity in cytosol extracts of the cerebral EC line was Ca(2+)-independent and required both NADPH and tetrahydrobiopterin. NOS activity was increased by TNF-alpha and IFN-gamma, and significantly reduced by tumor-cell-conditioned medium. These results suggest that rat colon-carcinoma cells may have developed a protective mechanism involving the release of (a) soluble factor(s) which inhibit(s) NO production by cerebral EC.
 ...
PMID:Tumor cells suppress cytokine-induced nitric-oxide (NO) production in cerebral endothelial cells. 752 97

Cellular constituents of heart muscle contain both constitutive and inducible nitric oxide (NO) signaling pathways that modulate the contractile properties of cardiac myocytes. The identities of the inducible NO synthase (iNOS) isoform(s) expressed in cardiac muscle, and of the specific cell types expressing iNOS activity, remain poorly characterized. We amplified a 217-base pair cDNA by reverse transcriptase-polymerase chain reaction from primary cultures of inflammatory cytokine-pretreated adult rat ventricular myocytes (ARVM) that was nearly identical to other iNOS cDNA sequences. Using this 217-base pair cDNA as a probe in Northern blots, we found no evidence of iNOS mRNA in control myocytes, but both interleukin-1 beta and interferon-gamma individually increased iNOS mRNA abundance in primary cultures of ARVM, with maximal expression at 12 h. The half-life of iNOS mRNA in actinomycin C1-treated cells was 4 h. Both dexamethasone and transforming growth factor-beta attenuated the induction of iNOS mRNA abundance and enzyme activity by IL-1 beta and INF gamma. Pretreatment with dexamethasone also abolished the induction of iNOS mRNA, but not the increase in GTP cyclohydrolase mRNA in purified cardiac myocytes from lipopolysaccharide-injected rats. In order to further characterize the specific cell type producing NO, we used a NO-specific porphyrinic/Nafion-coated microsensor to record NO release from a single, isolated ARVM pretreated with IL-1 beta and IFN gamma in L-arginine-depleted medium. NO release could be detected following microinjection of L-arginine in the vicinity of the cell juxtaposed to the NO microsensor, but not following microinjection of D-arginine, and not from ARVM pretreated with L-N-monomethylarginine. Cytokine-pretreated ARVM that had been maintained in L-arginine-depleted medium also exhibited a depressed contractile response to isoproterenol after addition of L-arginine, but not D-arginine. These results indicate that altered contractile function of cardiac myocytes following exposure to specific inflammatory cytokines is due to induction of myocyte iNOS.
 ...
PMID:Cytokine-inducible nitric oxide synthase (iNOS) expression in cardiac myocytes. Characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. 752 57

Nitric oxide synthase (NOS) catalyzes the production of nitric oxide (NO), a short-lived radical gas with physiological or pathophysiological roles in nearly every organ system. The inducible NO synthase (iNOS) is a high-output isoform compared to the two constitutive NOSs. The iNOS from murine macrophages tightly binds calmodulin as a subunit, and its activity is not dependent on exogenous calmodulin or elevated calcium. This iNOS is induced at the transcriptional level by bacterial lipopolysaccharide (LPS) and interferon-gamma. The promoter region of the murine iNOS gene contains at least 24 oligonucleotide motifs corresponding to elements involved in the binding of transcription factors in the promoters of other cytokine-inducible genes. Nuclear factor NF-kappa B/c-rel, interacting with cycloheximide-sensitive protein(s) and binding to the NF-kappa Bd site in the iNOS promoter, controls the induction of iNOS by LPS. However, iNOS is also regulated posttranscriptionally. Complex regulation of iNOS at multiple levels may reflect the dual role of iNOS in host defense and autotoxicity.
 ...
PMID:The high-output nitric oxide pathway: role and regulation. 752 16

NO is a major messenger molecule which regulates immunity and vascular tone, serves as a neurotransmitter and participates in wound healing. It has also been known to be increased in vivo by thermal injury. Urinary nitrate excretion and tissue levels of NO synthase activity were measured after a non-lethal thermal injury. Urinary nitrate excretion decreased by 90% 24-48 h after injury, but dramatically increased by 10-fold thereafter for 30-40 days after injury and remained elevated until the wound healed. This response was inhibited by a competitive inhibitor of NO synthase. These rates of urinary nitrate excretion suggest that NO production is dramatically affected by injury in a pattern that is distinct from that observed after lipopolysaccharide administration. On the basis of these findings, we suggest that the hyperdynamic cardiovascular and hypermetabolic responses seen to continue weeks after thermal injury could be a result of the autocrine and paracrine effects of NO generated locally within the tissues in addition to that generated by inflammatory cells.
 ...
PMID:Nitric oxide production is intensely and persistently increased in tissue by thermal injury. 752 6


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>