Protective effect of pristimerin against LPS-induced acute lung injury in mice
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Proinflammatory cytokine
Abstract A cell-by-cell analysis of the secretory ability of stimulated, individual alveolar macrophages (AMs) was performed through use of a tumor necrosis factor a (TNF-α) reverse hemolytic plaque assay. Two functional end points were measured: the percentage of AMs that were TNF-α secretors and the cumulative amount of TNF-α secreted by AMs (average plaque area, μm2). Lipopolysaccharide (LPS; 100 μg/ml) increased cumulative TNF-α release at both 7 and 20 h of incubation. On the other hand, a phorbol ester (phorbol myristate acetate, PMA) stimulated TNF-α release at 20 h of incubation but not at 7 h. Under nonstimulated culture conditions, 5-10% of all AMs released detectable TNF-α. PMA (but not LPS) induced a significant increase in the fraction of AMs capable of releasing TNF-α (15.1 ± 1.1% vs. 9.0 ± 1.6%, PMA vs. control, P < .05). Differences in the time course of secreted TNF-α, together with the recruiting effect of PMA, suggest that LPS and PMA target TNF-α- secretory subpopulations of AMs that differ in number and secretory characteristics.
Pulmonary alveolus
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These experiments provide an explanation for the observation that two intravenous injections of lipopolysaccharide (LPS) spaced 5 h apart in rabbits cause tumor necrosis factor/cachectin (TNF) levels to rise in the blood only after the first LPS injection. Herein we show that treatment of elicited peritoneal exudate rabbit macrophages (PEM) with two doses of LPS given 9 h apart results in a marked reduction in TNF production by the second LPS exposure. This state of hyporesponsiveness is a result of adaptation to LPS, is induced by LPS concentrations that are 1,000-fold less than required to induce TNF production (picograms vs. nanograms), is characterized by a decrease in LPS-induced TNF mRNA without any change in TNF mRNA half-life, is not changed by including indomethacin in cultures, and is specific for LPS since LPS-adapted cells display a TNF response to heat-killed Staphylococcus aureus that is at least as good as that observed in control PEM.
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Lethality and tumor necrosis factor production induced by different types of lipopolysaccharide were studied in naive (non-primed) rats during the late phase of endotoxin tolerance. The correlation with antilipopolysaccharide antibodies was also analyzed. No correlation was found between tumor necrosis factor levels and lipopolysaccharide-induced mortality in naive animals. Low-toxicity lipopolysaccharide preparations induced levels of tumor necrosis factor similar to those induced with more toxic types of lipopolysaccharide. Late tolerance was associated with progressively lower levels of lipopolysaccharide-induced tumor necrosis factor and increasing titers of antilipopolysaccharide antibodies after repeated injections of homologous lipopolysaccharide. During late endotonxin tolerance, a direct correlation between the lipopolysaccharide dose and peak tumor necrosis factor serum levels was found. We conclude that since tumor necrosis factor serum levels do not correlate with mortality, tumor necrosis factor alone cannot explain the lethal effect of lipopolysaccharide.
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Optimal activation of human monocytes in vitro for the biosynthesis of tumor necrosis factor was achieved only with complete S-form lipopolysaccharide. Endotoxin preparations with shorter carbohydrate chains or the lipid A component of lipopolysaccharide were not able to induce release of comparable amounts of tumor necrosis factor by monocytes under the conditions described. The same differences in the level of tumor necrosis factor mRNA were observed. Moreover, addition of these agents to appropriate monocyte-activating substances inhibited the production of tumor necrosis factor. The regulatory implications of this phenomenon are discussed.
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Macrophages are induced by LPS to release a number of products that determine the host response during gram negative sepsis. To examine the role of one such substance, tumor necrosis factor (TNF), in mediating LPS-induced injury, we employed a rabbit model of endotoxic shock to (a) determine the kinetics and extent of release of TNF into plasma after injection of LPS, and (b) to evaluate the protective effect of in vivo neutralization of LPS-induced TNF by prior infusion of anti-TNF antibody. TNF was maximally induced 45-100 min after injection of 10 micrograms i.v. parent Salmonella minnesota Re595 LPS or 250 micrograms Re595 LPS-HDL complexes. Maximal induction of TNF by LPS was associated with development of hypotension, focal hepatic necrosis, intravascular fibrin deposition and lethality. Based on (a) the peak levels of TNF observed in serum, 2.5 X 10(3) U/ml, (b) the specific activity of purified rabbit macrophage-derived TNF, 1 X 10(8) U/mg, and (c) the biphasic disappearance of intravenously injected purified TNF (t1/2 = 0.5 min, 11 min) we constructed a kinetic model showing that at least 130 micrograms of TNF (1.3 X 10(7) U) was released into plasma 30-200 min postinjection of LPS. Prior infusion of anti-TNF antibody (30-45 min before LPS injection) resulted in neutralization of the LPS-induced serum TNF activity and provided significant protection from the development of hypotension, fibrin deposition, and lethality. Thus, these results provide further evidence that TNF plays a central role mediating the pathophysiologic changes that occur during gram negative endotoxic shock.
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This work demonstrates the need for the continued presence of lipopolysaccharide (LPS) for tumor necrosis factor (TNF) production by thioglycollate-induced peritoneal macrophages. Removal of LPS at any time resulted in the abrupt cessation of further TNF production. The readdition of LPS resulted in further production of TNF but the yield was limited to the amount that would have been produced had the LPS not been removed.
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Lipid A
Strain (injury)
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Journal Article Polymyxin B Prevents Lipopolysaccharide-Induced Release of Tumor Necrosis Factor-α from Alveolar Macrophages Get access Dennis C. Stokes, Dennis C. Stokes 1 Please address requests for reprints to Dr. Dennis Stokes, Cardiopulmonary Division, St. Jude Children's Research Hospital, 332 N. Lauderdale, P.O. Box 318, Memphis, TN 38101-0318. Search for other works by this author on: Oxford Academic PubMed Google Scholar Jerry L. Shenep, Jerry L. Shenep Search for other works by this author on: Oxford Academic PubMed Google Scholar Marvin Fishman, Marvin Fishman Search for other works by this author on: Oxford Academic PubMed Google Scholar William K. Hildner, William K. Hildner Search for other works by this author on: Oxford Academic PubMed Google Scholar Gokul K. Bysani, Gokul K. Bysani Search for other works by this author on: Oxford Academic PubMed Google Scholar Karen Rufus Karen Rufus Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 160, Issue 1, July 1989, Pages 52–57, https://doi.org/10.1093/infdis/160.1.52 Published: 01 July 1989 Article history Received: 19 September 1988 Revision received: 03 March 1989 Published: 01 July 1989
Polymyxin B
Polymyxin
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