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

Sepsis is a systemic inflammatory response to a blood-borne infection that is associated with an extremely high rate of morbidity and mortality. The present study investigates the role of cyclooxygenase (COX)-2 in host responses to bacterial endotoxemia. After administration of Escherichia coli lipopolysaccharide, 50% of wild-type mice die within 96 h. COX-2 deficient mice displayed a dramatic improvement in survival with reduced leukocyte infiltration into critical organs (kidneys and lungs) and a blunted and delayed induction of the cytokine inducible genes nitric oxide synthase 2 and heme oxygenase-1. Translocation and activation of transcription factors important for signaling events during an inflammatory response, such as nuclear factor (NF)-kappaB, were also markedly reduced. While the absence of COX-2 did not alter the induction of several pro-inflammatory cytokines in tissue macrophages, induction of the anti-inflammatory cytokine IL-10 was exaggerated. Administration of IL-10 to wild-type mice reduced NF-kappaB activation. Taken together, our data suggest that COX-2 deficient mice are resistant to many of the detrimental consequences of endotoxemia. These beneficial effects occur, in part, by a compensatory increase in IL-10 that counterbalances the pro-inflammatory host response to endotoxemia.
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PMID:Cyclooxygenase-2-deficient mice are resistant to endotoxin-induced inflammation and death. 1273 99

The stress-inducible protein heme oxygenase-1 provides protection against oxidative stress and modulates pro-inflammatory cytokines. As the sepsis syndrome results from the release of pro-inflammatory mediators, we postulated that heme oxygenase-1 and its enzymatic product CO would protect against lethality in a murine model of sepsis. Mice treated with a lethal dose of lipopolysaccharide (LPS) and subsequently exposed to inhaled CO had significantly better survival and lower serum interleukin (IL)-6 and IL-1beta levels than their untreated counterparts. In vitro, mouse macrophages exposed to LPS and CO had significantly attenuated IL-6 production; this effect was concentration-dependent and occurred at a transcriptional level. The same effect was seen with increased endogenous CO production through overexpression of heme oxygenase-1. Mutation within the AP-1-binding site in the IL-6 promoter diminished the effect of CO on promoter activity, and treatment of macrophages with CO decreased AP-1 binding in an electrophoretic mobility shift assay. Electrophoretic mobility supershift assay indicated that the JunB, JunD, and c-Fos components of AP-1 were particularly affected. Upstream of AP-1, CO decreased JNK phosphorylation in murine macrophages and lung endothelial cells. Mice deficient in the JNK pathway had decreased serum levels of IL-6 and IL-1beta in response to LPS compared with control mice, and no effect of CO on these cytokine levels was seen in Jnk1 or Jnk2 genedeleted mice. In summary, these results suggest that CO provides protection in a murine model of sepsis through modulation of inflammatory cytokine production. For the first time, the effect of CO is shown to be mediated via the JNK signaling pathway and the transcription factor AP-1.
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PMID:Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1. 1285 51

Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme degradation, protects against oxidative stress, and shows potent anti-inflammatory effects. Oxidized phospholipids, which are generated during inflammation and apoptosis, modulate the inflammatory response by inducing the expression of several genes including HO-1. Here we investigated the signaling pathways and transcriptional events involved in the induction of HO-1 gene expression by oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) in human umbilical vein endothelial cells. OxPAPC up-regulated HO-1 mRNA and protein in a time- and concentration-dependent manner, whereas pro-inflammatory agents like TNF-alpha and lipopolysaccharide did not significantly induce HO-1 expression in human umbilical vein endothelial cells. Signaling pathways involved in the OxPAPC-mediated HO-1 induction included protein kinases A and C, as well as the mitogen-activated protein kinases p38 and ERK. The cAMP-responsive element-binding protein (CREB) was phosphorylated via these pathways in response to OxPAPC treatment and expression of a dominant-negative mutant of CREB inhibited OxPAPC-induced activity of a human heme oxygenase-1 promoter-driven luciferase reporter construct. We identified a cAMP-responsive element and a Maf recognition element to be involved in the transcriptional activation of the HO-1 promoter by OxPAPC. In gel shift assays we observed binding of CREB to the cAMP-responsive element after OxPAPC treatment. Induction of HO-1 expression by lipid oxidation products via CREB may represent a feedback mechanism to limit inflammation and associated tissue damage.
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PMID:Oxidized phospholipids induce expression of human heme oxygenase-1 involving activation of cAMP-responsive element-binding protein. 1452 7

The role of heme oxygenase-1 (HO-1) played in the inhibitory mechanism of flavonoids in lipopolysaccharide (LPS)-induced responses remained unresolved. In the present study, flavonoids, including 3-OH flavone, baicalein, kaempferol, and quercetin, induced HO-1 gene expression at the protein and mRNA levels in the presence or absence of LPS in RAW264.7 macrophages. This effect was associated with suppression of LPS-induced nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) protein expression. Hemin induced HO-1 protein expression and this was associated with the suppression of LPS-induced NO production and iNOS protein expression in a dose-dependent manner. In addition, an increase in bilirubin production was found in flavonoid- and hemin-treated cells. Hemin, at the doses of 10, 20, and 50 microM, dose-dependently stimulated the flavonoid (50 microM)-induced HO-1 protein expression, and enhanced their inhibitory effects on LPS-induced NO production and iNOS protein expression. Pretreatment of the HO-1 inhibitor, tin protoporphyrin (10 microM), attenuated the inhibitory activities of the indicated flavonoids on LPS-induced NO production. Morphologic analysis showed that 3-OH flavone, baicalein, kaempferol, quercetin, hemin, and tin protoporphyrin did not cause any change in cell viability in the presence or absence of LPS. In contrast, only 3-OH flavone showed a significant inhibition of cell growth using the MTT assay. Transfection of an HO-1 vector in macrophages (HO-1/RAW264.7) resulted in a 3-fold increase in HO-1 protein compared with that the parental RAW264.7 cells. NO production mediated by LPS in HO-1 over-expressed RAW264.7 cells (HO-1/RAW264.7) was significant less than that in parental RAW264.7 cells. 3-OH Flavone, baicalein, kaempferol, and quercetin showed a more significant inhibition on LPS-induced NO production in HO-1/RAW264.7 cells than in parental RAW264.7 cells. These results provide evidence on the role of HO-1 in the inhibition of LPS-induced NO production by flavonoids. A combination of HO-1 inducers (i.e. hemin) and flavonoids might be an effective strategy for the suppression of LPS-induced NO production.
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PMID:Inhibition of lipopolysaccharide-induced nitric oxide production by flavonoids in RAW264.7 macrophages involves heme oxygenase-1. 1456 92

Endotoxin-induced uveitis (EIU) is an animal model of acute ocular inflammation. Cytokines, chemokines, and nitric oxide (NO) have been reported to play important roles. We have determined whether heme oxygenase (HO)-1, a heat shock protein, can suppress EIU. EIU was induced by a footpad injection of lipopolysaccharide (LPS) in male Lewis rats. Hemin, an inducer of HO-1, was injected intraperitoneally 1 hr prior to the LPS injection. HO-1 and HO-2 expression in the iris-ciliary body (ICB) was studied by real time PCR and Western blot analysis. The number of infiltrating cells and the protein concentration in the aqueous humor (AqH) were evaluated by microscopy and by protein assay. The expression of inducible nitric oxide synthase (iNOS), interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and IL-1beta mRNA was determined by real time PCR. The concentration of nitrate plus nitrite, and levels of IL-6 and TNF-alpha in the AqH were also evaluated by Griess reagents and by enzyme-linked immunosorbent assay, respectively. The expression of HO-1 mRNA and protein, induced by LPS, was enhanced significantly by pre-injection of hemin (P<0.001). HO-2 was constitutively present in the ICB and was not up-regulated by LPS or by hemin. The number of infiltrating cells and the concentration of protein in the AqH was significantly elevated by LPS injection, and hemin significantly reduced the number of cells and the protein concentration (P<0.0001). The expression of iNOS and IL-6 mRNA and protein were down-regulated by hemin (P<0.001). Hemin is effective in inducing HO-1 and in reducing the ocular inflammation induced by LPS probably by down-regulating NO and pro-inflammatory cytokine expression.
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PMID:Protective role of heme oxygenase-1 against endotoxin-induced uveitis in rats. 1460 54

Post-traumatic inflammation and sepsis induce changes in the lung microvasculature causing increased permeability. Pericytes, contractile cells positioned abluminally to endothelial cells, play a role in regulating this response. An in vitro model of microvascular lung pericytes (MLP) was used to investigate the effect of inhibiting heme oxygenase-1 (HO-1), a stress-induced enzyme, in the presence of varying levels of lipopolysaccharide (LPS), a mediator in the initiation of inflammation, on pericyte contractility. Rat MLP were cultured on collagen gel matrices. Cells were exposed to three concentrations of LPS in the presence of zinc protoporphyrin IX (ZnPP-9), a known inhibitor of HO-1. After 24 hours, the surface area of the collagen disks was quantified, thereby measuring pericyte contraction. ZnPP-9 caused a significant attenuation of the LPS-induced relaxation of the pericytes (P < or = 0.003). The effects of ZnPP-9, however, depended on the concentration of LPS to which the pericytes were exposed. Greater concentrations of LPS decrease the attenuating power of ZnPP-9. The inhibition of HO-1 diminished MLP relaxation triggered by LPS. The effect of ZnPP-9, however, is dependent on the concentration of LPS to which the MLP are exposed, indicating its saturation. ZnPP-9 may antagonize the microvascular response to trauma.
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PMID:Inhibition of heme oxygenase-1 in microvascular lung pericytes diminishes at high concentrations of an inflammatory mediator. 1501 17

Acute inflammation is characterized by an accumulation of polymorphonuclear cells (PMNs), generation of reactive oxygen species, subsequent apoptosis of PMNs, and finally phagocytosis of apoptotic cells by macrophages. Recently, it has been demonstrated that during apoptosis oxidation of membrane phospholipids, especially phosphatidylserine, occurs. Moreover, we have shown that membrane vesicles released from apoptotic cells contain biologically active oxidized phospholipids. The involvement of oxidized phospholipids in the development of atherosclerosis, which is described as a chronic inflammatory disease, is increasingly recognized. These oxidized phospholipids were shown to induce several proinflammatory genes, such as monocyte chemoattractant protein 1 or interleukin-8, and it is hypothesized that lipid oxidation products also play a role in other chronic inflammatory disorders. On the other hand, oxidized phospholipids were shown to exert antiendotoxin effects by inhibiting lipopolysaccharide-induced signaling, representing a possible feedback loop during gram-negative infection. Additionally, it has been described that oxidized phospholipids are capable of inducing genes such as heme oxygenase-1 that are important for the resolution of acute inflammation. Moreover, oxidized phospholipids serve as recognition signals on apoptotic cells facilitating phagocytosis. In this review, we discuss the hypothesis that oxidized phospholipids generated in apoptotic cells (a) propagate chronic inflammation and (b) contribute to the resolution of acute inflammation.
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PMID:Apoptotic cells as sources for biologically active oxidized phospholipids. 1502 32

Epidemiologists have observed a positive association between human morbidity and mortality and the atmospheric concentrations of fine particulate matter (PM), but the mechanisms underlying the toxic effects of PM have not been elucidated. Various components of ambient PM have been implicated in toxicity (including ultrafine particles, transition metals, organics and oxidants). Our research focused on hydrogen peroxide (H2O2). We speculated that fine PM transports H2O2 into the lower lung, leading to tissue injury and to accumulation and activation of macrophages in these regions. The macrophages release cytotoxic mediators and proinflammatory cytokines that contribute to the pathogenesis of tissue injury. To test this hypothesis, we conducted studies to determine (1) whether tissue injury induced by aerosols is mediated by cytotoxic H2O2 carried into the lower lung by fine particles and (2) whether exposure of rats to fine PM leads to accumulation of activated macrophages in the lung. For our studies, systems were designed to generate model atmospheric fine PM and atmospheric peroxides consisting of an ammonium sulfate [(NH4)2SO4] aerosol (mass median diameter, 0.46 +/- 0.14 microm) and H2O2. We also constructed a 6-port nose-only exposure chamber. Female Sprague Dawley rats were exposed for 2 hours to aerosols consisting of (NH4)2SO4 (430 microg/m3), (NH4)2SO4 + 10, 20 or 100 ppb H2O2, vapor-phase H2O2 (10, 20 or 100 ppb), or particle-free air. Studies using oxygen-18 (18O)-labeled H2O2 were conducted to validate the transport of H2O2 into the lower lung with (NH4)2SO4. Rats were killed immediately (0 hours) or 24 hours after exposure. Compared with control animals, inhalation of (NH4)2SO4 and H2O2, alone or in combination, had no major effect on cell number or viability, protein content, or lactate dehydrogenase (LDH) levels in bronchoalveolar lavage (BAL) fluid collected either immediately or 24 hours after exposure. However, electron microscopy revealed that a larger number of neutrophils in pulmonary capillaries adhered to the vascular endothelium, especially in lungs of rats exposed to (NH4)2SO4 + H2O2. Inhalation of (NH4)2SO4 + H2O2 was also found to be associated with altered macrophage functional activity. Thus, exposing rats to (NH4)2SO4 + 20 ppb H2O2 or 20 ppb H2O2 alone caused a level of tumor necrosis factor alpha (TNF-alpha) production by lung macrophages that was higher than in controls. This higher level was observed immediately after exposure and persisted for at least 24 hours. Greater TNF-alpha production was also detected 24 hours after exposure to (NH4)2SO4 + 10 ppb H2O2. Immediately after rats inhaled (NH4)2SO4 + 10 ppb H2O2 or 20 ppb H2O2 alone, we also observed a transiently higher production of superoxide anion (O2-) by alveolar macrophages. Macrophages isolated 24 hours after exposure to 20 ppb H2O2 also produced larger quantities of superoxide anion. In contrast, immediately after exposure, macrophages from rats exposed to (NH4)2SO4 + 10 ppb H2O2 or to 20 ppb H2O2 alone generated less nitric oxide (NO). Reduced nitric oxide production was also observed 24 hours after exposure to (NH4)2SO4 + 10 ppb H2O2 or to 10 or 20 ppb H2O2 alone. Reduced nitric oxide production may have been due to superoxide anion-driven formation of peroxynitrite (ONOO-) anions. In this regard, nitrotyrosine, an in vivo marker of peroxynitrite, was detected in lung tissue immediately after rats were exposed to (NH4)2SO4 + H2O2 or to H2O2 alone (10 or 20 ppb). We also found that alveolar macrophages from rats exposed to (NH4)2SO4 + H2O2 showed a greater expression of the antioxidant enzyme heme oxygenase-1 (HO-1) when stimulated with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Similar results were observed after exposure of rats to an organic peroxide aerosol (cumene hydroperoxide). Taken together, the results of our studies demonstrate that biological effects of inhaled H2O2 are augmented by fine PM. Moreover, tissue injury induced by (NH4)2SO4 + H2O2 may be related to altered production of cytotoxic mediators by alveolar macrophages. Determining the relevance of these toxicologic results to human health will be important in future studies for evaluating the risk of exposure.
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PMID:Peroxides and macrophages in the toxicity of fine particulate matter in rats. 1503 94

Acute graft-versus-host disease (aGVHD) remains one of the main obstacles after allogeneic bone marrow transplantation (BMT). Using a well-established mouse BMT model in which aGVHD is induced across a haploidentical mismatch, we show that the expression of heme oxygenase-1 (HO-1) can be induced by cobalt-protoporphyrin IX (CoPP) in aGVHD target organs such as liver and bowel and that the induction of HO-1 before BMT results in improved overall survival and reduced aGVHD. Serum levels of proinflammatory cytokines were markedly reduced in CoPP-treated animals. Recipients displayed less damage to the intestinal mucosa, and this resulted in reduced serum lipopolysaccharide levels at day 6 after transplantation. Peritoneal cells and CD45(+) liver cells isolated from mice that received transplants strongly expressed HO-1 and displayed a reduction in the expression of activation markers such as CD11b, CD80, and major histocompatibility complex class I. This resulted in reduced T-cell activation ex vivo. These results demonstrate that the induction of HO-1 before high-dose conditioning protects the host in multiple ways and effectively ameliorates aGVHD.
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PMID:Induction of heme oxygenase-1 before conditioning results in improved survival and reduced graft-versus-host disease after experimental allogeneic bone marrow transplantation. 1520 67

Inducible nitric oxide (NO) synthase (iNOS), heme oxygenase (HO)-1, and indoleamine 2,3-dioxygenase (IDO) are simultaneously expressed in murine macrophages stimulated with interferon (IFN)-gamma and lipopolysaccharide (LPS). NO produced by iNOS suppresses IDO expression and also induces HO-1 expression. The antioxidant 3-hydroxyanthranilic acid (HA), one of metabolites of tryptophan via IDO pathway, has been previously reported to suppress iNOS expression. Because HO-1 expression can suppress iNOS expression, we investigated whether HA could suppress iNOS expression by affecting HO-1 expression in murine RAW 264.7 macrophages stimulated with IFN-gamma plus LPS. Treatment with exogenous HA dose-dependently suppressed iNOS expression and coincidently enhanced HO-1 expression. This suppressive effect of HA on iNOS expression was reversed by blocking HO-1 activity, and proven to be due to carbon monoxide (CO) produced by HO-1. In addition, either blocking of iNOS activity or addition of exogenous CO further enhanced IDO expression and activity. These results show for the first time that HA is able to suppress iNOS expression by enhancing HO-1 expression, thereby resulting in further increases in IDO expression and activity.
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PMID:3-Hydroxyanthranilic acid, one of metabolites of tryptophan via indoleamine 2,3-dioxygenase pathway, suppresses inducible nitric oxide synthase expression by enhancing heme oxygenase-1 expression. 1524 10


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