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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current evidence suggests that bleomycin toxicity may be attributable to its DNA degradative activity possibly via generation of free radicals and O2 metabolites as mediators. Since lipopolysaccharide (LPS) has been known to provide protection against O2 toxicity, which is correlated with increased activity of O2 metabolite-detoxifying enzymes, the effect of this agent on bleomycin-induced pulmonary fibrosis was examined. Endotracheal bleomycin administration caused increased lung collagen synthesis. A single intraperitoneal injection of LPS (500 micrograms/kg) at day zero significantly decreased these increases. Total bleomycin-induced lung collagen increase was also significantly reduced. LPS alone had no significant effect on total lung catalase activity. Glutathiione peroxidase activity, however, was significantly decreased by 15.8% compared to untreated animals at 2 days after LPS treatment and remained unchanged at other time points. In addition, superoxide dismutase activity was significantly elevated by 30% above untreated animals only at 14 days after LPS administration and remained unchanged at other time points. Endotracheal bleomycin administration alone caused significant reductions in catalase activity at 2 days and 2 weeks after treatment, whereas glutathione peroxidase activity increased above control untreated animals at 2 and 4 weeks, respectively. Superoxide dismutase activity was unaffected by bleomycin treatment. Pretreatment with LPS before bleomycin prevented these reductions or caused increases in the activities of these enzymes at 2 days. Glutathione peroxidase was increased and was significantly greater than those animals treated with bleomycin alone. Catalase also was higher in the LPS plus bleomycin group (by 22.2%, p less than 0.05) than the bleomycin group alone. Compared to the effects on lung collagen synthesis and content, LPS treatment resulted in much less dramatic changes in total lung antioxidant enzyme activities. This discrepancy between the intensity of LPS effects on lung O2 metabolite-detoxifying enzymes and that on pulmonary fibrosis implies that the LPS-ameliorating effect on pulmonary fibrosis could not be totally explained by increased ability to detoxify O2 metabolites. Rather, the data would favor the possibility that LPS inhibits bleomycin-induced pulmonary fibrosis either by its known immunosuppressive effects or some other unknown mechanism. The former would be in agreement with previous data which suggest that an intact immune response is necessary for complete expression of the fibrogenic response to bleomycin.
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PMID:Inhibition of bleomycin-induced pulmonary fibrosis by lipopolysaccharide. 620 76

Peritoneal macrophages from C3HeB/FeJ mice became cytotoxic for 6C3HED lymphosarcoma cells, P815 mastocytoma cells, and L-929 fibroblasts when treated with the calcium ionophore, A23187, at concentrations ranging from 1.0 to 20 microM. The effect of A23187 on other activation processes was also tested. It was found that A23187 and lipopolysaccharide (LPS) acted synergistically, but no consistent synergy with macrophage-activating factor (MAF) was observed. Cytotoxic activity (M phi-CF) was found in cellfree supernatants from M phi activated by A23187 or LPS. Furthermore, these two activating agents synergize in the production of M phi-CF. The cytotoxic activity of the crude material was not blocked by catalase or protease inhibitors. Fractionation of supernatants by high pressure liquid chromatography has shown that there was a peak of cytotoxic activity with a m.w. of approximately 45,000. Interestingly, L-929 cells were 30-fold more sensitive to M phi-CF than a lymphotoxin-resistant subline of L-929.
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PMID:Mechanism of macrophage-mediated cytotoxicity: production of a soluble cytotoxic factor. 641 64

Guinea pig peritoneal macrophages, when activated for cytotoxicity by the calcium ionophore A23187 or lipopolysaccharide, produce a cytotoxic factor [macrophage cytotoxic factor (M phi-CF)] that is not blocked by catalase or protease inhibitors. Fractionation of culture supernates containing M phi-CF by gel filtration revealed one peak of cytotoxic activity of Mr approximately 45,000, the same as guinea pig lymphotoxin (LT). Antiserum prepared against purified guinea pig LT completely neutralized the cytotoxic activity of M phi-CF. In addition, the cytotoxic factor in guinea pig tumor necrosis serum was found to have a Mr of 45,000 and was neutralized by anti-LT. Thus, M phi-CF is physicochemically and immunochemically similar to LT and tumor necrosis factor, if not identical. To investigate the role of M phi-CF in macrophage-mediated cytotoxicity, anti-LT was added to A23187- or lipopolysaccharide-activated macrophages before addition of L-929 target cells. In 10 of 16 experiments, the inhibition of macrophage-mediated cytotoxicity was 100%. In the others, cytotoxicity was blocked partially, the lowest inhibition being 49%. The effectiveness of inhibition appeared to be inversely related to the intensity of macrophage activation. These results indicate that M phi-CF plays a significant role in macrophage-mediated cytotoxicity but involvement of another mechanism cannot be excluded.
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PMID:Macrophage-mediated cytotoxicity: role of a soluble macrophage cytotoxic factor similar to lymphotoxin and tumor necrosis factor. 660 18

Spleen cells of diabetes-prone BB Wistar rats were found to generate excessively low proliferative responses, and interleukin 2 (IL-2) levels in response to T-dependent mitogens. This abnormality was not due solely to abnormal T cell numbers since: (a) addition of BB spleen cells of BB splenic macrophages to normal major histocompatibility complex (MHC)-matched Wistar Furth (WF) spleen cells resulted in severe suppression of concanavalin A (Con A)-, phytohemagglutinin (PHA)-, and pokeweed mitogen (PWM)-mediated proliferation, and IL-2 production; (b) macrophage depletion from BB spleen cells, but not B cell or T cell depletion, removed completely the suppressive effects of BB cells on WF cells; (c) macrophage depletion greatly enhanced the response of BB lymphocytes to T-dependent mitogens. Although suppressor macrophages could also be found in the spleen of WF control rats they were present in much smaller numbers than in the spleen of BB rats. The suppressive effect of BB macrophages was partially reduced by addition of the prostaglandin synthetase inhibitor indomethacin to cultures. Furthermore, indomethacin (but not catalase or PMA) considerably augmented IL-2 secretion of Con A-stimulated BB spleen cells, but had little effect on WF spleen cells. In contrast, prostaglandins E1 and E2 (PGE1 and PGE2) suppressed IL-2 production. While IL-2 secretion was severely depressed in BB rats unstimulated and lipopolysaccharide (LPS)-stimulated IL-1 secretion by splenic macrophages was normal. BB macrophages did not inactivate IL-2. Low IL-2 production and macrophage-mediated suppression were features of all BB rats tested.
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PMID:Immune dysfunction in diabetes-prone BB rats. Interleukin 2 production and other mitogen-induced responses are suppressed by activated macrophages. 660 15

When human alveolar macrophages (AM) lavaged from healthy donors were incubated in medium with or without lipopolysaccharide (LPS) or muramyl dipeptide, they released a factor(s) responsible for tumor cell killing. The activity of the tumor cytolytic factor(s), called TCF, was determined by radioactive release assay. Human AM released variable amounts of TCF into the culture medium without any stimulation, but the release was stimulated significantly by LPS (0.1 micrograms/ml) or muramyl dipeptide (1 micrograms/ml). Maximal production of TCF by the AM was detected in the supernatant after treatment for 3 hr with LPS, and the extent of TCF release correlated with the density of AM. In cultures with LPS, the ability of activated AM to secrete TCF was maintained for 48 hr but was lost by 96 hr. After its loss, the ability to produce TCF could be restored by a second treatment with LPS. Full expression of lysis by TCF to lyse tumor cells required its interaction with tumor cells for at least 24 hr. TCF destroyed human allogeneic tumor cell lines but did not affect nonneoplastic cell lines. TCF activity was resistant to treatment with protease inhibitors, superoxide dismutase, or catalase and to heating at 70 degrees for 1 hr, but it was labile on heating at 100 degrees for 10 min. The tumoricidal activity in the supernatant of activated human AM indicates a potential effector mechanism by which AM kill neoplastic cells.
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PMID:Production of a tumor cytolytic factor(s) by activated human alveolar macrophages and its action. 669 69

We have examined the role of the glutathione redox cycle as an antioxidant defense mechanism in cultured bovine and human endothelial cells by disrupting the glutathione redox cycle at several points. Endothelial glutathione reductase was selectively inhibited with 1,3-bis(chloroethyl)-1-nitrosourea (BCNU). Cellular stores of reduced glutathione were depleted by reaction with diethylmaleate (DEM) or 1-chloro-2,4-dinitrobenzene (CDNB) or by inhibition of glutathione synthesis with buthionine sulfoximine (BSO). Whereas several strains of untreated bovine and human endothelial cells were resistant to lysis by enzymatically generated hydrogen peroxide, BCNU-treated cells were readily lysed in a time- and dose-dependent manner. Glucose-glucose oxidase-mediated lysis of BCNU-treated bovine endothelial cells was catalase-inhibitable and directly related to BCNU concentration and endogenous glutathione reductase activity. Pretreatment of bovine endothelial cells with BCNU did not potentiate lysis by distilled water, calcium ionophore, lipopolysaccharide, or hypochlorous acid. Depletion of cellular reduced glutathione by reaction with DEM or CDNB or by inhibition of glutathione synthesis by BSO also potentiated endothelial lysis by enzymatically generated hydrogen peroxide. Inhibition of endothelial glutathione reductase by BCNU or depletion of reduced glutathione by BSO increased endothelial susceptibility to lysis by hydrogen peroxide generated by phorbol myristate acetate-activated neutrophils. We conclude that the glutathione redox cycle plays an important role as an endogenous antioxidant defense mechanism in cultured endothelial cells.
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PMID:Glutathione redox cycle protects cultured endothelial cells against lysis by extracellularly generated hydrogen peroxide. 670

The mechanisms by which macrophages kill ingested microorganisms were explored using Candida albicans and Candida parapsilosis. The results indicate that efficient macrophage candidacidal activity depends upon the generation of oxygen metabolites by the phagocytic cell: (a) peritoneal macrophages from mice infected with bacillus Calmette-Guerin (BCG) or injected intraperitoneally with lipopolysaccharide (LPS) released more superoxide anion (0(2)(-)) during phagocytosis of candida and killed candida better than did resident macrophages; (b) cells of the macrophage-like line J774.1, which released negligible amounts of O(2)(-), could ingest the candida normally but not kill them; (c) killing of candida by resident, LPS- elicited, and BCG-activated macrophages was inhibited by agents that scavenge O(2)(-), hydrogen peroxide (H(2)0(2)), hydroxyl radical (x OH), and singlet oxygen; and (d) all three macrophage types killed C. parapsilosis more effectively than C. albicans, and (7. parapsilosis stimulated a more prompt and vigorous burst of macrophage oxygen consumption and 0(2)(-) release than did C. albicans. Macrophages ingested C. parapsilosis slightly more quickly than C. albicans, but phagocytosis of both strains was equivalent by 60 min of incubation. Although C. albicans contained higher concentrations of the oxygen-metabolite scavengers superoxide dismutase and catalase, neither fungal species scavenged 0(2)(-) or H(2)0(2) effectively; and C. albicans was killed more easily than C. parapsilosis by a xanthine oxidase system that generates primarily H(2)O(2) at pH 7, or 0(2)(-) and x OH at pH 10. Thus, the decreased killing of C. albicans appears to result primarily from the capability of this species to elicit less vigorous stimulation of macrophage oxidative metabolism. This capability may have general relevance to the pathogenicity of microorganisms.
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PMID:Macrophage microbicidal activity. Correlation between phagocytosis-associated oxidative metabolism and the killing of Candida by macrophages. 740 Jul 57

Reactive oxygen metabolites are believed to be important mediators of sepsis- or lipopolysaccharide (LPS)-induced adult respiratory distress syndrome. EUK-8 is a novel, synthetic, low-molecular-weight salen-manganese complex that exhibits both superoxide dismutase and catalase activities in vitro. We hypothesized that treatment with EUK-8 would ameliorate pulmonary dysfunction in a porcine model of LPS-induced adult respiratory distress syndrome. At T = -18 h, pigs received an intravenous priming dose of LPS (20 micrograms/kg). Anesthetized ventilated swine were randomized to receive 1) no further treatment (n = 5); 2) LPS (250 micrograms/kg from T = 0 to 60 min, n = 6); 3) LPS and a low dose of EUK-8 (10-mg/kg bolus at T = -15 min and 1 mg/kg.h from T = 0 to 240 min, n = 6) or 4) LPS and a higher dose of EUK-8 (10-mg/kg bolus and 3 mg/kg.h, n = 6). Treatment with EUK-8, particularly at the higher dose, significantly attenuated many of the features of LPS-induced acute lung injury, including arterial hypoxemia, pulmonary hypertension, decreased dynamic pulmonary compliance and pulmonary edema. LPS caused an increase in lung tissue malondialdehyde content that was abrogated in both EUK-8-treated groups. EUK-8 treatment had no effect on circulating plasma levels of tumor necrosis factor-alpha, thromboxane B2 or 6-keto-prostaglandin F1 alpha. We conclude that EUK-8 prevents many of the manifestations of LPS-induced adult respiratory distress syndrome in pigs by detoxifying reactive oxygen metabolites without affecting the release of other important proinflammatory mediators.
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PMID:EUK-8, a synthetic superoxide dismutase and catalase mimetic, ameliorates acute lung injury in endotoxemic swine. 747 69

Enhanced formation of nitric oxide (NO) by both the constitutive and the inducible isoforms of NO synthase (NOS) has been implicated in the pathophysiology of a variety of diseases, including circulatory shock. Non-isoform-selective inhibition of NO formation, however, may lead to side effects by inhibiting the constitutive isoform of NOS and, thus, the various physiological actions of NO. S-Methylisothiourea sulfate (SMT) is at least 10- to 30-fold more potent as an inhibitor of inducible NOS (iNOS) in immunostimulated cultured macrophages (EC50, 6 microM) and vascular smooth muscle cells (EC50, 2 microM) than NG-methyl-L-arginine (MeArg) or any other NOS inhibitor yet known. The effect of SMT on iNOS activity can be reversed by excess L-arginine in a concentration-dependent manner. SMT (up to 1 mM) does not inhibit the activity of xanthine oxidase, diaphorase, lactate dehydrogenase, monoamine oxidase, catalase, cytochrome P450, or superoxide dismutase. SMT is equipotent with MeArg in inhibiting the endothelial, constitutive isoform of NOS in vitro and causes increases in blood pressure similar to those produced by MeArg in normal rats. SMT, however, dose-dependently reverses (0.01-3 mg/kg) the hypotension and the vascular hyporeactivity to vasoconstrictor agents caused by endotoxin [bacterial lipopolysaccharide (LPS), 10 mg/kg, i.v.] in anesthetized rats. Moreover, therapeutic administration of SMT (5 mg/kg, i.p., given 2 hr after LPS, 10 mg/kg, i.p.) attenuates the rises in plasma alanine and aspartate aminotransferases, bilirubin, and creatinine and also prevents hypocalcaemia when measured 6 hr after administration of LPS. SMT (1 mg/kg, i.p.) improves 24-hr survival of mice treated with a high dose of LPS (60 mg/kg, i.p.). Thus, SMT is a potent and selective inhibitor of iNOS and exerts beneficial effects in rodent models of septic shock. SMT, therefore, may have considerable value in the therapy of circulatory shock of various etiologies and other pathophysiological conditions associated with induction of iNOS.
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PMID:Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiourea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase. 752 23

The first line of defence against natural infection by Histoplasma capsulatum (Hc) consists of bronchoalveolar macrophages (BAM) and an early inflammatory response in the lungs. Little is known about the interaction of BAM and Hc, consequently we studied murine BAM in vitro to assess their role in the pulmonary defence in histoplasmosis. A short-term 3-h assay was used to measure fungicidal activity of control BAM and interferon-gamma (IFN-gamma) plus lipopolysaccharide (LPS)-activated BAM. Fungistatic activity of BAM was determined with a 24-h assay. A method devised for measuring colony-forming units (CFU) of non-ingested non-adherent and adherent ingested yeast cells of Hc in BAM cocultures was used. Activated BAM killed Hc (reduced inoculum CFU by 25 +/- 12%; n = 4). The fungicidal activity of BAM was abrogated by 0.2 mM NG-monomethyl-L-arginine (NMMA) or catalase but not by superoxide dismutase. In fungistatic assays activated BAM inhibited multiplication of Hc by 61 +/- 4% (n = 3) compared with cocultures with control BAM. However, Hc multiplied 100% more in control BAM cocultures than in medium alone. Data indicated that this was due to advantages that Hc has in the intracellular environment. Only NMMA inhibited fungistatic activity of activated BAM. In experiments with peritoneal macrophages (PM), results similar to those with BAM were obtained. In conclusion, activated BAM and PM kill yeast cells of Hc by a mechanism dependent on hydrogen peroxide and products of the nitric oxide synthase (NOS) pathway, whereas fungistasis depends only on products of the NOS pathway.
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PMID:Antifungal mechanisms of activated murine bronchoalveolar or peritoneal macrophages for Histoplasma capsulatum. 755 2


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