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)

In an attempt to elucidate the effect of lipoxygenase inhibitors on hepatic injury, we investigated D-galactosamine (GalN)-treated C57BL/6 mice receiving an intravenous (i.v.) injection of lipopolysaccharide (LPS)-activated autologous spleen cells. As compared with control spleen cells, the number of monocytes in the spleen cells isolated from LPS-treated mice and their oxidative free radical production increased markedly. Oxygen radical production by the dish-adherent cells (macrophage-rich population) was enhanced a further 4-fold. Although hepatotoxicity was not demonstrated in mice treated with 20 mg GalN alone, marked hepatic injury was found in the GalN-treated mice with a supplementation of LPS-activated spleen cells. The dish-adherent cells aggravated this hepatic injury, in contrast to minor hepatotoxicity by the nonadherent cells. Oxygen radical production by LPS-activated spleen cells was markedly reduced by the lipoxygenase inhibitors (azelastine, ketotifen and AA861). Hepatotoxicity was scarcely detected in the GalN-treated mice with a supplementation of the LPS-activated spleen cells which had been previously treated with lipoxygenase inhibitors. From these results, LPS-activated spleen macrophages contributed to hepatic injury induced by GalN, and lipoxygenase inhibitors which reduced oxygen radical production by the activated cells, protected against macrophage-induced hepatic injury in mice.
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PMID:Leukotriene inhibitors modulate hepatic injury induced by lipopolysaccharide-activated macrophages. 210 47

Prostaglandins and leukotrienes are ubiquitous mediators of a wide variety of physiologic and immunologic effects in liver function and disease. Although the biochemical, synthetic and catabolic pathways of these compounds from arachidonic acid are well known, their cellular mechanisms of action are less well understood. Numerous studies have demonstrated the role for leukotrienes in the pathogenesis and the protective action of PG in experimental animal models of liver injury. These have included models of liver cell damage due to ischemia, galactosamine, carbon tetrachloride, and lipopolysaccharide. More importantly, the results of these studies have led to the demonstration of protective properties of 16, 16 dimethyl PGE2 (dm PGE2) in a mouse model of viral hepatitis. These results have led to the use of IV PGE1 in the treatment of patients with fulminant viral hepatitis, where 71% overall survival was observed as well as in the setting of primary non function and recurrent hepatitis B following liver transplantation. While the mechanisms of prostaglandin hepatic protection are not well understood, it has been demonstrated that dm PGE2 abrogates the induction of tumour necrosis factor, leukotriene B4 (LTB4) and procoagulant activity by macrophages as well as attenuating the expression of major histocompatibility class antigens on the surface of hepatocytes, and may inhibit viral replication. Finally, prostaglandins are known to play a role in the renal dysfunction associated with cirrhosis and fulminant hepatic failure, and therefore further studies of these agents in the pathophysiology and treatment of liver diseases and their complications are warranted.
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PMID:Eicosanoids and the liver. 213 47

Multiple extrapulmonary organ system failures increase mortality, permeability edema, and alveolar inflammation during gram-negative sepsis because of abnormal regulation of host inflammatory responses. We tested the hypothesis that acute hepatocytic injury induced by the selective hepatotoxin, D-galactosamine (GalN), augments mortality and amplifies pulmonary microvascular permeability to albumin and neutrophilic influx after administering Escherichia coli lipopolysaccharide (LPS) 24 h later by impairing the metabolism of endogenously synthesized products of arachidonic acid. We determined the lung extravascular leak of 125I-human serum albumin measured at multiple time points after LPS and enumerated polymorphonuclear leukocytes (PMNs) in bronchoalveolar lavage fluid (BALF). Because the liver is important in prostaglandin (PG) and leukotriene (LT) metabolism, we measured plasma concentrations of 6-keto-PGF1 alpha and thromboxane B2 (TxB2) in addition to paired plasma BALF concentrations of LTB4 and BALF LTC4 60 min and 24 h after LPS. We further assessed the protective effects of a single 20-mg/kg injection given intraperitoneally (i.p.) of the LTA4 synthetase inhibitor, diethylcarbamazine (DEC). After 400 mg/kg GalN, LPS at 2.5 or 1.25 mg/kg i.p. increased mortality (p less than 0.001), albumin leak 60 and 90 min after LPS (p less than 0.05), plasma 6-keto-PGF1 alpha, TxB2, and LTB4 levels and BALF LTC4 within 60 min (p less than 0.05). LTB4 and LTC4 levels in BALF 24 h later were similarly increased (p less than 0.05) as were bronchoalveolar PMNs (p less than 0.001). DEC improved mortality and albumin leak (p less than 0.001), reduced lung influx of PMNs and peripheral leukocytosis (p less than 0.05), attenuated plasma LTB4 and BALF LTC4 levels 60 min after LPS (p less than 0.05), and decreased BALF LTB4 and LTC4 at 24 h (p less than 0.05), but was associated with higher plasma 6-keto-PGF1 alpha and TxB2 values at 60 min. Changes in eicosanoid levels and modulation of responses by DEC in this model suggest that impaired metabolism of endogenously synthesized leukotriences by the damaged liver underlies these phenomena. We conclude that this mechanism may enhance septic lung injury during acute liver dysfunction.
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PMID:Effects of D-galactosamine-induced acute liver injury on mortality and pulmonary responses to Escherichia coli lipopolysaccharide. Modulation by arachidonic acid metabolites. 218 85

Mice pretreated by intravenous injection of 42 mg/kg of the serine protease inhibitor alpha 1-antitrypsin prior to a hepatotoxic dose of D-galactosamine/lipopolysaccharide (GalN/LPS) were fully protected against hepatitis. Pretreatment with alpha 1-antitrypsin with doses up to 300 mg/kg at different times failed to protect galactosamine sensitized animals against tumor necrosis factor alpha (TNF alpha)-induced hepatitis. No bioactive TNF alpha was detectable in serum of mice protected against GalN/LPS-induced hepatitis by pretreatment with alpha 1-antitrypsin. In contrast, abundant amounts of TNF were found in sera of GalN/LPS-treated control animals. It is concluded that a serine protease sensitive to alpha 1-antitrypsin provides bioactive TNF alpha by proteolytic cleavage of a TNF alpha precursor.
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PMID:In vivo evidence for protease-catalysed mechanism providing bioactive tumor necrosis factor alpha. 222 15

Intravenous injection of lipopolysaccharide and D-galactosamine, at doses of 0.2 micrograms/kg and 800 mg/kg, respectively, elicited massive hepatic necrosis within 24 hr in C3H/HeN mice. The plasma L-alanine aminotransferase (ALT, E.C. 2.6.1.2) or L-aspartate aminotransferase (AST, E.C. 2.6.1.1) activities at this point reached more than 2,000 IU/L. However, overt hepatic injury as evaluated by the plasma aminotransferase activities did not develop in mice in which only lipopolysaccharide or only D-galactosamine was injected. No tumor necrosis factor-like activities could be detected in the plasma of galactosamine- and lipopolysaccharide-injected mice as determined by the assay of cytotoxicity to highly tumor necrosis factor-sensitive L-P3 cells through the experimental period of 24 hr. However, passive immunization against mouse tumor necrosis factor-alpha with polyvalent rabbit anti-mouse tumor necrosis factor-alpha antiserum, which was able to neutralize the cytotoxic effects of recombinant mouse tumor necrosis factor-alpha on L-P3 cells, could protect the mice from the development of hepatic injury in a dose-dependent manner. Simultaneous injection of recombinant human tumor necrosis factor-alpha, instead of lipopolysaccharide, with 800 mg/kg of D-galactosamine in lipopolysaccharide-resistant C3H/HeJ mice sensitized the animals more than one thousand-fold to the development of hepatic injury. The livers appeared to be morphologically similar to those of galactosamine- and lipopolysaccharide-injected C3H/HeN mice.
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PMID:Involvement of tumor necrosis factor-alpha in development of hepatic injury in galactosamine-sensitized mice. 222 17

Many pathological effects of gram-negative bacteria are produced by their cell wall-derived lipopolysaccharides (LPSs). Differing pathogenicity of gram-negative LPSs, however, may depend on their capacities to induce cytokines. Thus, we studied the lethal toxicity of four nonenterobacterial LPSs and compared it with their capacity to induce mononuclear cell (MNC)-derived interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF). Unstimulated MNC did not release these cytokines. LPS from the phototrophic strain Rhodobacter capsulatus 37b4 elaborated little toxicity in galactosamine-treated mice (10 micrograms of LPS per mouse was the 100% lethal dose [LD100]) and induced IL-1 and IL-6 release only at high concentrations (10 to 50 micrograms of LPS per ml). R. capsulatus LPS failed to induce TNF activity even at the highest concentration tested (100 micrograms of LPS per ml). In contrast, LPS derived from Pseudomonas diminuta NCTC 8545 or the nodulating species Bradyrhizobium lupini DSM 30140 and Rhizobium meliloti 10406 expressed lethal toxicity (LD100, 1,000, 100, and 10 ng per mouse, respectively) and induced IL-1 or IL-6 (10 to 100, 10, and 1 ng of LPS per ml, respectively) at concentrations 1,000- to 10,000-fold lower than effective levels of R. capsulatus LPS. LPSs from P. diminuta, B. lupini, and R. meliloti also stimulated TNF production and release. MNC accumulated cell-associated IL-1 activities under circumstances in which released activity was readily detected. The cells contained only scant IL-6 activity, indicating release of this mediator rather than intracellular accumulation. Antisera to the respective cytokines inactivated biological activities of the samples selectively. The R. capsulatus LPS inhibited cytokine induction by LPS from P. diminuta, B. lupini, and R. meliloti in coincubation experiments. These results show that the in vivo lethality of the LPSs tested correlates with the induction of monocyte-derived cytokines in vitro. The results of this study suggest that the different lethality of various LPSs from gram-negative bacteria may be due to the differential ability of these LPSs to induce cytokine production.
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PMID:Cytokine induction by lipopolysaccharide (LPS) corresponds to lethal toxicity and is inhibited by nontoxic Rhodobacter capsulatus LPS. 222 45

The biological and endotoxic activities of protective antigens (PAgs) prepared by the chloroform-methanol-water method from Leptospira interrogans serovars lai, copenhageni and canicola were examined. The PAg preparations did not show a local Shwartzman reaction in the rabbits at doses of 100 micrograms and 50 micrograms/site and lethal toxicity to galactosamine-sensitized mice at the dose of 12.5 micrograms to 50 micrograms/mouse. PAgs exhibited a weak cytotoxic action on peritoneal exudate macrophages of C3H/HeJ and C3H/HeN mice at the dose of 500 micrograms/ml in vitro, but did not show cytotoxicity for BHK-21 cells kidney cells of the Syrian hamster, CHO-K1, ovary cells of the Chinese hamster, and CHL, lung cells of the Chinese hamster, at doses of 5 and 500 micrograms/ml. Gelation activity in the Limulus test was only observed at PAg concentrations over 100 ng/ml, which dose was 10,000 times that of lipopolysaccharide (LPS) of Escherichia coli O55:B5. Furthermore, an adjuvant activity of PAgs was not observed in the production of anti-sheep red blood cell antibody in mice. Mitotic conversion of spleen cells from C3H/HeJ and C3H/HeN mice was observed by the addition of PAgs in vitro. These results indicated that the biological properties of PAgs were different from those of LPS prepared from gram-negative enterobacteria, that PAgs had no endotoxic activity and that the biological safety of PAgs as vaccine was proved.
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PMID:Biological activities and endotoxic activities of protective antigens (PAgs) of Leptospira interrogans. 226 Oct 63

Although administration of 100 mg galactosamine caused severe hepatic injury in C3H/HeN mice, splenectomy reduced the grade of this hepatotoxicity. However, this hepatic injury was scarcely detected in the endotoxin-resistant C3H/HeJ mice. In addition, in contrast to high lethality in C3H/HeN mice with a combined administration of galactosamine and endotoxin, splenectomy rendered C3H/HeN mice slightly resistant to this treatment. Further resistance was demonstrated in C3H/HeJ mice. In an attempt to clarify the role of endotoxin-responsive spleen cells in the pathogenesis of hepatic injury, we investigated galactosamine-induced hepatic injury by transfer of lipopolysaccharide-treated C3H/HeN or C3H/HeJ spleen cells. Both oxygen-derived free radical production and the proportion of macrophages in spleen cells were markedly enhanced in C3H/HeN mice after an intraperitoneal injection of lipopolysaccharide. Further increase in oxidative free radical production was found in the dish-adherent cells (macrophages). These enhancements were not demonstrated in lipopolysaccharide-treated C3H/HeJ spleen cells. Although hepatic injury was not demonstrated in both C3H/HeN and C3H/HeJ mice treated with 35 mg galactosamine alone, severe hepatotoxicity was found in these galactosamine-treated mice when they received lipopolysaccharide-activated C3H/HeN spleen cells, especially macrophages. Simultaneous administration of superoxide dismutase with the activated spleen cells reduced the grade of hepatic injury. On the other hand, hepatic injury was not demonstrated in the galactosamine-treated C3H/HeN or C3H/HeJ mice when they received lipopolysaccharide-treated C3H/HeJ spleen cells, although 3H-galactosamine incorporation into hepatocytes was nearly identical in both C3H/HeN and C3H/HeJ mice. These results suggest that oxidative free radicals of lipopolysaccharide-responsive macrophages could contribute to the pathogenesis of galactosamine-induced hepatic injury.
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PMID:Role of endotoxin-responsive macrophages in hepatic injury. 230 97

Biological activity of lipopolysaccharides (LPSs) separated from Bordetella, i.e., B. pertussis (Bp), B. parapertussis (Bpp) and B. bronchiseptica (Bbs), was determined and compared with that of an Escherichia coli LPS as a control. Two Bp-LPS preparations showed marked biological activities comparable to those of E. coli LPS in terms of lethal toxicity in galactosamine-sensitized mice, pyrogenicity in rabbits, mitogenicity in C3H/He spleen cell cultures, macrophage activation and tumor necrosis factor-inducing activity. All the activities except mitogenicity of two Bpp-LPS preparations were lower than or comparable to those of E. coli LPS. Activities stronger than or comparable to those of E. coli LPS were observed in two Bbs-LPS preparations. Among six LPS preparations from Bordetella tested, a Bbs-LPS from L3 strain exhibited the most intensive activities.
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PMID:Biological properties of lipopolysaccharides isolated from Bordetella. 232 4

Antitumor activity, mitogenicity, and lethal toxicity of chemically synthesized lipid A analogs, acylglucosamine-4- or -6-phosphate with the alpha, beta-hydroxyacyl, acyloxyacyl, or hydroxyacyloxacyl groups at the C-2 and C-3 positions, were examined. Meth A fibrosarcoma cells (5 X 10(5)) were inoculated subcutaneously into BALB/c mice on day 0, and six compounds (50 micrograms/mouse) were administered intravenously on days 7 and 9. Although the antitumor activity of these compounds was weaker than that of natural lipopolysaccharide (LPS) or the synthetic lipid A analog (506) of Escherichia sp type, all groups exhibited tumor inhibition rates of 40% to 50% and delayed tumor growth. Six compounds, with the exception of compound A-173 (with the hydroxytetranoyl group at the C-2 and C-3 positions), were capable of increasing the incorporation of [3H]thymidine into cultured splenocytes of C57BL/6 mice, and caused lethal toxicity in C57BL/6 mice sensitized with galactosamine. However, these compounds had lower toxicity than bacterial LPS (about 500- to 1,000-fold). Compounds A-172 and A-174, which have the same structure except for the C-4 or C-6 position of the phosphate group, exerted similar antitumor activity, mitogenicity, and lethality. The results discussed above indicate that the biologic activity of these compounds correlates with the carbon number of fatty acid but is not affected by the different location of the phosphate group. Furthermore, it seems that the difference between the alpha, beta-hydroxy position of fatty acid and the R or S configuration does not alter the biologic effects.
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PMID:Antitumor activity against Meth A fibrosarcoma and biologic activities of synthetic monosaccharide analogs of lipid A in mice. 236 54


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