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)

The requirements for activation of anti-mycobacterial and anti-listerial activity of human monocytes were investigated. Human monocytes could be activated to display enhanced anti-mycobacterial activity by a 24-h treatment with lipopolysaccharide. The mediator induced by this treatment was identified as being tumour necrosis factor-alpha (TNF-alpha). Addition of recombinant TNF-alpha (rTNF-alpha) to the cultures of human monocytes for 24 h yielded comparable results (minimal dose required for induction of anti-mycobacterial activity, 10 U ml). Addition of anti-TNF-alpha antibody completely abrogated the effect. A similar treatment protocol failed to activate enhanced anti-listerial activity. To trigger anti-listerial activity, sequential treatment of human monocytes with rTNF-alpha and IL-2 was required. Treatment of monocytes with 10 U ml rTNF-alpha for 24 h followed by incubation in the presence of 200 U/ml of IL-2 for an additional 24 h yielded a reduction of listerial growth which was moderate but statistically significant (P less than 0.001). The activation of monocytes observed with rTNF-alpha/IL-2 treatment was (i) dependent on both cytokines; (ii) sequence dependent (i.e. when IL-2 was added prior to rTNF-alpha, no effect was observed); and (iii) absent in cells treated with one cytokine only. Enhancement of anti-listerial activity by sequential use of cytokines was not accompanied by an increase in oxidative burst, which indicated that oxidative mechanisms were not the reason for the observed Listeria monocytogenes growth restriction. Further support for this hypothesis was obtained after interferon-gamma treatment of human monocytes which led to an augmented PMA-inducible release of active oxygen radicals, but was not paralleled by growth restriction of L. monocytogenes. Our results indicate that TNF-alpha plays a crucial role in the activation of monocytes for growth restriction of intracellular microbes. Activation of human monocytes to restrict the growth of the facultative intracellular bacteria Mycobacterium avium intracellulare and L. monocytogenes, however, follows different patterns, the initial trigger in both cases being provided by TNF-alpha-induced signals.
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PMID:Induction of anti-mycobacterial and anti-listerial activity of human monocytes requires different activation signals. 164 23

Biological agents such as the interferons (IFNs) or lipopolysaccharides (LPSs) can prime phagocytic cells to generate increased amounts of oxygen metabolites upon exposure to various stimuli. The priming of human peripheral blood monocytes and alveolar macrophages (AM) by recombinant IFN-beta ser (rIFN-beta ser) and rIFN-gamma for an enhanced respiratory burst was compared. Both rIFN-beta ser and rIFN-gamma increased phorbol myristate acetate-stimulated superoxide anion generation by AM in a dose-dependent fashion. rIFN-beta ser was capable of priming AM for an enhanced superoxide anion release nearly as well as rIFN-gamma. In contrast, rIFN-beta ser was much less effective as a priming agent for monocytes when compared to either its effect on AM or to the priming effect of rIFN-gamma on monocytes. The respiratory burst of IFN-exposed AM was not inhibited by co-incubation with low concentrations of LPS. However, the ability of IFN to augment superoxide anion release by cells simultaneously exposed to LPS in comparison to superoxide anion generation by cells exposed to LPS only was attenuated.
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PMID:Priming of human alveolar macrophages and blood monocytes for superoxide anion release by interferons and lipopolysaccharide. 166 31

Bleomycin (BLM) has been successfully used to treat a number of human neoplasms. The main toxicity associated with BLM therapy is an acute pulmonary inflammation that can culminate in diffuse chronic fibrosis. The effect of BLM-induced pulmonary inflammation on the cytostatic activity of alveolar macrophages (AM) was investigated using AM obtained from rats that had been previously treated with BLM. Bronchoalveolar lavage fluid was collected at selected time intervals following a single fibrogenic dose of intratracheally administered BLM (3.6 mg/kg). AM obtained 12 to 72 h following intratracheal BLM (BLM-AM) caused cytostasis of murine leukemia L1210 cells in co-culture, whereas AM obtained from saline-treated controls were not cytostatic. These results indicate that the growth-inhibitory activity of the AM was related to the pulmonary inflammation. Cytostatic activity in control AM could be induced by in vitro exposure to lipopolysaccharide (5 micrograms). When RBC were added to the AM-L1210 co-culture, the cytostatic activity of the BLM-AM was abrogated. The fact that chemical treatment of the RBC with sodium nitrite and potassium cyanide or N-ethylmaleimide did not alter the ability of the RBC to abrogate AM cytostatic activity suggests that the RBC is not acting as a scavenger of oxygen radicals. In contrast, the addition of FeSO4 to the AM-L1210 co-culture mimicked the effect of RBC addition. Aconitase, an iron-sulfur-containing enzyme necessary for mitochondrial respiration, is decreased in L1210 cells that have been co-cultured with BLM-AM but not when the co-cultures also contain RBC. These results suggest that (a) pulmonary inflammation induces cytostatic activity in AM, (b) the alteration of iron homeostasis plays an important role in this cytostatic process, and (c) RBC can prevent this cytostatic activity.
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PMID:Effect of erythrocytes on alveolar macrophage cytostatic activity induced by bleomycin lung damage in rats. 169 May 96

The cytosol fraction of J774-1 murine macrophages activated with lipopolysaccharide (LPS) + interferon-gamma (IFN-gamma) was found to nitrosate a wide range of secondary and tertiary amines. The reaction was dependent on L-arginine and NADPH. The optimal pH for nitrosation was 7.2-7.3. Nitrosation was inhibited by arginine derivatives such as NG-monomethyl-L-arginine and NG-nitro-L-arginine, well-known inhibitors of nitric oxide (NO) synthase. These results indicate that nitrosation is mediated by NO synthase, which catalyzes formation of NO and L-citrulline from L-arginine. Nitrosamine formation also required oxygen and was inversely correlated with the basicity of nitrosatable amines. The nitrosation was inhibited by oxyhemoglobin, an NO trapping agent, and enhanced by superoxide dismutase, which stabilizes NO. LPS + IFN-gamma induced approximately 500-600 times greater nitrosation activity than that of non-activated macrophages. Macrophages treated with LPS alone exhibited 3-4 times greater nitrosation activity than untreated macrophages, whereas macrophages treated with IFN-gamma alone did not show enhanced nitrosation activity. A combination of the cytosols from macrophages treated with LPS alone and IFN-gamma alone did not nitrosate morpholine as rapidly as the cytosol of macrophages treated with both compounds together. The activity for forming L-citrulline and nitrite/nitrate from L-arginine was markedly induced by treatment with either LPS alone or LPS + IFN-gamma but not with IFN-gamma. Those results suggest that some other factor(s) in addition to NO synthase is involved for efficient nitrosation by the macrophage cytosol. This factor(s) was not induced in macrophages by either LPS- or IFN-gamma alone, but was induced only in the presence of the two compounds.
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PMID:L-arginine-dependent formation of N-nitrosamines by the cytosol of macrophages activated with lipopolysaccharide and interferon-gamma. 171 76

Intravenous lipopolysaccharide (LPS) decreases superior mesenteric arterial blood flow and increases ileal mucosal permeability in pigs. We tested the hypothesis that these phenomena can be ameliorated by pretreatment and posttreatment with ibuprofen. Pentobarbital-anesthetized immature swine were mechanically ventilated (fraction of inspired oxygen, 0.5) and infused with Ringer's lactate (RL) solution (0.8 mL/kg per minute). Animals in group RL (n = 10) received no other interventions. Animals in group RL + LPS (n = 15) were infused with LPS (50 micrograms/kg) from a time range equal to 0 through 60 minutes. Animals in group RL + LPS + ibuprofen (n = 10) were similarly infused with LPS, but in addition, they received ibuprofen (10 mg/kg at -30 minutes and 10 mg/kg per hour from -30 through 210 minutes). Intestinal permeability was assessed by measuring plasma-to-lumen clearances of two hydrophilic probes (chromium 51-labeled edetic acid monohydrate [EDTA] and urea) and by expressing the results as a clearance ratio (CEDTA/CUREA). Survival was 100%, 67%, and 100% in groups RL, RL + LPS, and RL + LPS + ibuprofen, respectively. Among survivors only, CEDTA/CUREA increased significantly over time in both endotoxic groups, but not in nonendotoxic controls. Treatment with ibuprofen transiently blocked LPS-induced mesenteric hypoperfusion. These data indicate that mediators other than cyclooxygenase-derived metabolites of arachidonic acid are responsible for the adverse effect of LPS on mesenteric permeability to hydrophilic solutes in this porcine model.
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PMID:Ibuprofen improves survival but does not ameliorate increased gut mucosal permeability in endotoxic pigs. 173 50

Normally, supply-dependency of oxygen uptake (VO2) is not demonstrable unless oxygen delivery (DO2) is less than a critical value (DO2crit) below which VO2 is linearly dependent upon DO2. Because recent evidence suggests that VO2 is pathologically supply-dependent in endotoxic or septic animals and humans, we sought to determine whether 1) pathological systemic and/or mesenteric oxygen extraction (O2EXT) defects occur in a porcine model of endotoxicosis and 2) arterial lactate and ileal intramucosal pH (pHI) serve as useful markers of supply-dependency of VO2 in endotoxic animals. Normal (group I, n = 11) and endotoxic (group II, n = 8) anesthetized pigs were subjected to graded hemorrhage. Endotoxicosis was induced by infusing Escherichia coli lipopolysaccharide (150 micrograms/kg bolus at t = 0 min and 20 micrograms/kg-hr at t = 60 min). From t = 0-60 min, pigs in group II were resuscitated with hetastarch and blood (12 ml/kg each). Hemorrhage was initiated at t = 0 min or t = 70 min in groups I and II, respectively. DO2crit was determined by a modified "dual-line" regression method. Systemic DO2crit was 12.9 +/- 0.9 ml/kg-min in group I and 16.9 +/- 1.3 ml/kg-min in group II (P less than .05). Systemic O2EXT at DO2crit was similar in both groups. Arterial lactate concentration at DO2crit was significantly higher in endotoxic pigs (group I, 2.64 +/- 0.29 mM; vs. group II, 3.88 +/- 0.45 mM; P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Systemic and mesenteric O2 metabolism in endotoxic pigs: effect of graded hemorrhage. 174 60

Recombinant mouse interleukin 10 (IL-10) was exceedingly potent at suppressing the ability of mouse peritoneal macrophages (m phi) to release tumor necrosis factor alpha (TNF-alpha). The IC50 of IL-10 for the suppression of TNF-alpha release induced by 0.5 microgram/ml lipopolysaccharide was 0.04 +/- 0.03 U/ml, with as little as 1 U/ml suppressing TNF-alpha production by a factor of 21.4 +/- 2.5. At 10 U/ml, IL-10 markedly suppressed m phi release of reactive oxygen intermediates (ROI) (IC50 3.7 +/- 1.8 U/ml), but only weakly inhibited m phi release of reactive nitrogen intermediates (RNI). Since TNF-alpha is a T cell growth and differentiation factor, whereas ROI and RNI are known to inhibit lymphocyte function, it is possible that m phi exposed to low concentrations of IL-10 suppress lymphocytes. m phi deactivated by higher concentrations of IL-10 might be permissive for the growth of microbial pathogens and tumor cells, as TNF-alpha, ROI, and RNI are major antimicrobial and tumoricidal products of m phi. IL-10's effects on m phi overlap with but are distinct from the effects of the two previously described cytokines that suppress the function of mouse m phi, transforming growth factor beta and macrophage deactivation factor. Based on results with neutralizing antibodies, all three m phi suppressor factors appear to act independently.
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PMID:Macrophage deactivation by interleukin 10. 174 84

A number of agents capable of interfering with oxidative events were found to inhibit, in a dose-dependent manner, DNA synthesis in isolated human peripheral blood lymphocytes stimulated with phytohaemagglutinin, or phorbol myristate acetate plus ionomycin. These inhibitory substances were: the iron chelators desferrioxamine and desferrithiocin; the electron acceptor ferricyanide; the anti-oxidant nordihydroguaiaretic acid; ebselen, an agent with glutathione peroxidase-like activity; and diphenylene iodonium, an inhibitor of NADPH-oxidase. The actions of desferrioxamine and desferrithiocin were abolished by prior saturation with iron. Ferrocyanide was much less active in inhibiting human lymphocyte DNA synthesis than its redox partner ferricyanide. Desferrioxamine, ferricyanide and nordihydroguaiaretic acid also inhibited lipopolysaccharide-initiated DNA synthesis in mouse splenocytes in vitro. The common property of these structurally dissimilar agents is their ability to prevent formation of, or detoxify, reactive oxygen species. Thus, the data are consistent with an obligatory role for reactive oxygen formation in human T-cell and mouse B-cell activation at a stage prior to DNA synthesis.
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PMID:Interference with oxidative processes inhibits proliferation of human peripheral blood lymphocytes and murine B-lymphocytes. 176 47

There is considerable evidence to implicate aggressive species of oxygen in the pathogenesis of organ dysfunction consequent to sepsis and septic shock. The inflammatory process appears to participate ubiquitously in this setting. A characteristic of inflammation is the involvement of activated neutrophils and their generation of aggressive oxygen species. Such species may both directly injure cells proximal to the oxidant generating cells, and may inactivate any proteolytic mechanisms normally protective against proteolytic injury caused by neutrophil elastase and other proteolytic enzymes released during inflammation. The offending agent in sepsis is most commonly envisioned as bacterial lipopolysaccharide, or endotoxin. Infusion of endotoxin into animals can reproduce much of the pathophysiology of sepsis and septic shock. In addition, administration of endotoxin to cultured cells, particularly endothelial cells, can cause responses consistent with a sequence of events that occurs in intact animals and humans. In both experimental models, it appears that aggressive oxygen species are important actors in the scenario eventuating in cell or organ injury. Of importance, the toxic consequences of these free radicals probably occurs in relatively protected spaces, including microenvironments created by close adherence between inflammatory cells and endothelial cells and the cell interior. For those reasons, the potential for antioxidants as therapy should include consideration of the volume of distribution of such substances. It is probably important that antioxidants access excluded spaces including cell interiors in order to have their maximum effect in this setting. We have studied ina preliminary way the effects of n-acetyl-cysteine, a highly permeable free radical scavenger and anti-oxidant, in patients with established ARDS.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Oxygen radicals--an important mediator of sepsis and septic shock. 179 73

Although the shock syndrome is recognized as a form of "mediator poisoning", a plethora of details is hardly converging into a coherent concept of chronological and molecular order. As a model for organ failure in septic shock, three alternative experimental approaches with a common pathology are presented: When galactosamine-sensitized mice receive either lipopolysaccharide or leukotriene D4 or tumor necrosis factor alpha they develop fulminant hepatitis within few hours with a lethal outcome within one day. Detailed pharmacological intervention studies allow to conclude that endotoxin-induced leukotriene D4 release induces a transient ischemia by the known vasoconstrictive action of this eicosanoid. A following reperfusion/reoxygenation phase gives rise to superoxide formation which inactivates alpha 1 proteinase inhibitor. Thus a serine protease becomes active which is responsible for the processing of a monocytic tumor necrosis factor alpha precursor to be released into the circulation after proteolytic cleavage. By this sequence the final central mediator of shock and sepsis becomes systematically abundant. The concept arising from these studies reconciles previously known findings and provides a link between the role of reactive oxygen species in inflammation, the balance of proteases and antiproteases in the extracellular space and the release of the cytokine tumor necrosis factor in sepsis and shock.
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PMID:Reactive oxygen species, antiproteases, and cytokines in sepsis. 179 93


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