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 treatment of septic shock remains a major problem in surgical practice. Current research on the pathogenesis of the sepsis syndrome focuses on the effects of the lipopolysaccharide constituents of bacterial endotoxin. Evidence suggests that endotoxin induces a whole-body inflammatory response that in turn mediates organ damage, eventually leading to multiorgan failure. The first organ in which failure is usually apparent is the lung, with the appearance of non-cardiogenic pulmonary oedema as part of the adult respiratory distress syndrome. Inflammatory cells involved in lung injury include neutrophils and macrophages, which release mediators such as elastase, oxygen radicals and cytokines. This review summarizes current experimental work on how endotoxin leads to lung injury, based on its effects in animals and patients. Present knowledge suggests that future treatment of septic shock might involve inhibiting the body's inflammatory response to endotoxin. Possible ways of doing this are discussed.
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PMID:Endotoxin, septic shock and acute lung injury: neutrophils, macrophages and inflammatory mediators. 833 Jan 85

Monoclonal antibody against human tumor necrosis factor alpha (TNF MAb) prevents death induced by intravenous gram-negative bacteria or lipopolysaccharide (LPS) in primates. Although these studies have demonstrated that TNF plays a prominent role in the development of lethal septic shock, exploration of dose-response relationships and possible mechanisms of protection have been limited. We addressed these questions in a series of experiments conducted in E. coli-challenged pigs. First, we determined that TNF MAb neutralized the cytotoxic activity found in septic pig plasma and in culture media from pig monocytes incubated with LPS. Second, we demonstrated that pretreatment with TNF MAb promotes survival, in a dose-dependent fashion, in an otherwise lethal E. coli bacteremic pig model. The results of the survival study highly correlate (r = 0.96, P < 0.01) the presence of TNF in the circulation with mortality. In an additional series of physiologic monitoring experiments designed to delineate possible mechanisms of protection, the authors demonstrate that TNF MAb pretreatment abrogates the prolonged leukopenia, thrombocytopenia, and microvascular leakiness resulting from intravenous bacterial challenge and maintains arterial blood pressure while diminishing pulmonary edema. These findings may provide a mechanism whereby neutralization of TNF systemically affords protection against the lethal sequelae of bacteremia.
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PMID:Efficacy of monoclonal antibody against human recombinant tumor necrosis factor in E. coli-challenged swine. 144 53

TNF is a major mediator in the pathogenesis of endotoxic shock, and its inhibition has a protective effect in various animal models of sepsis or endotoxin (lipopolysaccharide, LPS) toxicity. LPS treatment also induces an oxidative damage mediated by increased production of reactive oxygen intermediates. N-Acetylcysteine (NAC) is an antioxidant and a precursor of the synthesis of glutathione (GSH) and was reported to protect against LPS toxicity and LPS-induced pulmonary edema. In this study we investigated the effect of NAC on TNF production and LPS lethality in mice. The results indicated that oral administration of NAC protects against LPS toxicity and inhibits the increase in serum TNF levels in LPS-treated mice. The inhibition was not confined to the released form of TNF, since NAC also inhibited LPS-induced spleen-associated TNF. On the other hand, the inhibitor of GSH synthesis, DL-buthionine-(SR)-sulfoximine (BSO), had the opposite effect of potentiating LPS-induced TNF production, and this was associated with a decrease in liver GSH levels. Repletion of liver GSH with NAC reversed this effect. NAC was also active in inhibiting TNF production and hepatotoxicity in mice treated with LPS in association with a sensitizing dose of Actinomycin D. These data indicate that GSH can be an endogenous modulator of TNF production in vivo. On the other hand, NAC pretreatment did not inhibit other effects of LPS, particularly induction of serum IL-6, spleen IL-1 alpha, and corticosterone, in the same experimental model, suggesting that the observed effect could be specific for TNF.
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PMID:N-acetylcysteine and glutathione as inhibitors of tumor necrosis factor production. 154 68

The passage of different-sized marker molecules over the lower respiratory tract into the blood circulation during pulmonary inflammation induced by dextran, endotoxin [i.e., lipopolysaccharide from Escherichia coli (LPS)], or ferritin was assessed in the rat. Bovine immunoglobulin G (BIgG, mol wt = 150,000 Da), bovine serum albumin (BSA, mol wt = 67,000 Da), and the nonapeptide 1-deaminocysteine-8-D-arginine vasopressin (dDAVP, mol wt = 1,067 Da) were used as permeability markers after intratracheal instillation. The pathophysiological indexes of a proceeding lung inflammation were increased total cell number, changed leukocyte proportions and increased total protein content obtained in bronchoalveolar lavage, and lung edema formation shown as an increased lung wet-dry weight difference. Intratracheal instillation of dextran induced a moderate neutrophil invasion into the lungs but had no effect on the passage of the different markers over the lungs (BIgG 1.8 +/- 0.6%, BSA 3.5 +/- 1.2%, dDAVP 26.1 +/- 20.7%) compared with control rats instilled with the markers alone (1.8 +/- 0.4%, 4.1 +/- 1.3%, 20.0 +/- 3.8%, respectively). Endotoxin administration resulted in markedly higher lavage cell counts and lung edema concomitantly with an increased lung passage of the markers (3.2 +/- 0.9%, 22.0 +/- 6.1%, 33.3 +/- 12.0%, respectively; P less than 0.01-P less than 0.001). The highest marker passage was obtained when the inflammation was most severe, i.e., after ferritin administration (17.6 +/- 2.3%, 60.0 +/- 6.7%, 41.6 +/- 6.9%, respectively; P less than 0.001), which resulted in markedly elevated lavage cell numbers and protein content as well as edema formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lung to blood passage of different-sized molecules during lung inflammation in the rat. 172 3

Endotoxin (lipopolysaccharide or LPS) inhalation has been implicated in increased pulmonary edema, most likely due to activation of an inflammatory response. The purpose of this study was to determine the cell types in the lung responsible for binding inhaled lipid A from Enterobacter agglomerans LPS. Five-hour exposures of aerosolized lipid A resulted in measurable pulmonary edema in hamsters, as determined by the accumulation of lung water. Immunocytochemistry was used to localize the inhaled lipid A in the cell types in the lung. Alveolar macrophages had decreased levels of lipid A as compared to unexposed controls, suggesting a possible metabolism by the macrophages. In vitro exposure of macrophages to lipid A resulted in a time-dependent clearance of lipid A which was inversely related to its concentration. Alveolar macrophages thus appear to be responsible for the removal of inhaled lipid A in this model and may initiate the physiological events which bring about pulmonary edema.
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PMID:Immunocytochemical determination of the role of alveolar macrophages in endotoxin processing in vitro and in vivo. 176 44

We used a selective leukotriene (LT) D4/E4 receptor antagonist (LY 203647) to investigate the role of cysteinyl LTs as mediators of several important pathophysiological events in a porcine model of endotoxic shock. Pentobarbital-anesthetized pigs (11.8-17.5 kg) were mechanically ventilated with 100% O2. Pigs in groups I (n = 10), IIA (n = 10), and IIB (n = 5) were infused with Escherichia coli lipopolysaccharide (LPS; 250 micrograms/kg) from time (t) = 0-20 min. Pigs in group III (n = 3) were normal controls. All pigs were resuscitated from t = 0-240 min with Ringer lactate (0.8 ml.kg-1.min-1). Pigs in group I received no further treatment. At t = 30 min, groups IIA and IIB were injected with LY 203647 (30 mg/kg) and were started on an infusion of the compound at 10 (group IIA) or 30 mg.kg-1.h-1 (group IIB). Delayed treatment with LY 203647 significantly (P less than 0.05) and persistently ameliorated LPS-induced pulmonary hypertension. The compound also abrogated LPS-induced pulmonary edema, as assessed by gravimetrically determined lung extravascular wet-to-dry weight ratios. Despite its beneficial effect on pulmonary edema, delayed treatment with LY 203647 did not improve arterial oxygenation. Delayed treatment with LY 203647 transiently improved mesenteric perfusion. These data suggest that cysteinyl LTs are important mediators in porcine endotoxicosis.
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PMID:Delayed treatment with an LTD4/E4 antagonist limits pulmonary edema in endotoxic pigs. 185 25

Fluid resuscitation is complicated in hypotensive septic patients by their susceptibility to pulmonary edema. This problem was evaluated in the ovine model of endotoxemia with a chronic lung lymph fistula. Escherichia coli endotoxin (lipopolysaccharide, 1.5 micrograms/kg) was given intravenously over 30 minutes. Group M (n = 9) continued to receive baseline fluids (2 mL/kg/h), while group R (n = 6) received 7 mL/kg/h of Ringer's lactate. After an initial drop in cardiac index, animals in both groups developed a hyperdynamic state. The fall in mean arterial pressure seen in group M was absent from group R. The higher fluid volume resulted in a rise in left atrial pressure and pulmonary microvascular pressure. The lung lymph flow and permeability index were elevated in both groups but were higher in group R. The calculated filtration coefficient showed a threefold increase in both groups. Augmented fluid resuscitation during endotoxemia resulted in an elevated interstitial fluid flux and permeability index secondary to an increase in pulmonary microvascular pressure and greater surface area of the injured microvascular beds being perfused.
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PMID:Pulmonary microvascular changes following fluid resuscitation in an ovine model of endotoxemia. 327 89

There is a need for pharmacological agents for the treatment of pulmonary edema associated with the adult respiratory distress syndrome. Therefore, we examined the effects of isozyme-selective cyclic AMP phosphodiesterase (cAMP PDE) inhibitors, as well as aminophylline and dexamethasone, on the pulmonary edema, protein leakage into the airways and airway neutrophilia induced by aerosolized lipopolysaccharide (LPS) in intact guinea pigs. Twenty-four hours after LPS exposure lung wet/dry weight ratios increased from 4.9 +/- 0.004 to 5.8 +/- 0.02. Rolipram (PDE4 selective), CI-930 (PDE3 selective), aminophylline and dexamethasone (given p.o. 1 hr before and 4 hr after LPS exposure) inhibited pulmonary edema formation with ED50 values of 1.7, 0.5, 31 and 2.8 mg/kg, respectively. Maximum inhibition occurred with rolipram at 10 mg/kg (70 +/- 17%), CI-930 at 10 mg/kg (101 +/- 4%), aminophylline at 50 mg/kg (88 +/- 14%) and dexamethasone at 3 mg/kg (64 +/- 6%). Denbufylline and milrinone also inhibited pulmonary edema formation at 10 mg/kg i.p., supporting the inhibition of PDE4 and PDE3 as the mechanisms of action of rolipram and CI-930, respectively. Rolipram, CI-930, aminophylline and dexamethasone (at maximum doses for inhibiting pulmonary edema) inhibited the 3-fold increase in bronchoalveolar lavage albumin concentration 24 hr after LPS exposure (42 +/- 14%, 98 +/- 2%, 70 +/- 9% and 53 +/- 13%, respectively). However, none of these compounds (at maximum doses for inhibiting pulmonary edema) inhibited the corresponding 400-fold increase in lavage neutrophil counts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of lipopolysaccharide-induced pulmonary edema by isozyme-selective phosphodiesterase inhibitors in guinea pigs. 747 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

Granulocyte colony-stimulating factor (G-CSF) stimulates the production and function of neutrophils (PMNs). Administration of G-CSF to non-neutropenic animals has been shown to improve survival in experimental models of infection, but PMNs have been implicated as mediators of acute lung injury induced by lipopolysaccharide (LPS) or bacteremia. Thus G-CSF-induced neutrophilia might be deleterious in sepsis. To investigate this possibility, we studied four groups of pigs: G+E50 (n = 6) were pretreated for 5 days with recombinant bovine (rb) G-CSF (5 micrograms/kg/day) and then challenged with LPS (50 micrograms/kg); NS+E50 (n = 6) were similarly pretreated with saline and challenged with LPS (50 micrograms/kg); E250 (n = 6) were not pretreated and were infused with a larger dose of LPS (250 micrograms/kg); RL (n = 7) were controls infused with lactated Ringer's solution. Pretreatment with rbG-CSF increased the peripheral absolute neutrophil count approximately fivefold (p < 0.05 vs. RL group). Comparisons of the NS+E50 and G+E50 groups showed that pretreatment with rhG-CSF did not affect LPS-induced alterations in mean arterial blood pressure or arterial oxygenation. Indices of pulmonary injury also were similar in these two groups, although pulmonary edema and protein leakage into alveoli were greater in the E250 group. We conclude that G-CSF-induced neutrophilia does not adversely effect physiologic responses to LPS in pigs.
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PMID:Effect of granulocyte colony-stimulating factor on systemic and pulmonary responses to endotoxin in pigs. 768 31


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