UNIPROT:P43026 - FACTA Search

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

Aspiration of gastric contents is one of leading causes of the acute respiratory distress syndrome (ARDS). The pathogenesis of acid aspiration-induced acute lung injury is well understood. Less clear is why patients who have suffered acid aspiration are susceptible to ARDS. We studied the effects of acid instillation on the inflammatory response to subsequent lipopolysaccharide (LPS) challenge in rats. Instillation of acid into the right lung worsened the pathology induced by LPS that was administered 24 h after acid instillation. This included worsened oxygenation, increased pulmonary edema, increased production of tumor necrosis factor-alpha (TNF-alpha) and cytokine-induced neutrophil chemoattractant, neutrophil accumulation and mobilization to the alveolar spaces, and nitric oxide (NO) production. Of interest, neutrophil mobilization, NO production, and protein permeability were also magnified in the left lung. These effects were attenuated by administration of the protein tyrosine kinase (PTK) inhibitors genistein and tyrphostin AG556. These data suggest that acid instillation primes the rat to enhance the inflammatory response to subsequent endotoxin challenge and that at least part of the augmented inflammatory response depends on PTK.
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PMID:Acid instillation enhances the inflammatory response to subsequent lipopolysaccharide challenge in rats. 1102 46

Endotoxin is thought to contribute to pulmonary hyperresponsiveness in byssinosis, asthma, and the acute respiratory distress syndrome (ARDS). The aim of this study was to elucidate the mechanism of this phenomenon in the isolated, blood-free perfused mouse lung. Perfusion with lipopolysaccharide (LPS) had no effect on pulmonary resistance or pulmonary artery pressure, but induced airway hyperreactivity (AHR) to methacholine (MCh) and pulmonary vascular hyperreactivity (VHR) to platelet-activating factor (PAF). Blockade of the thromboxane/endoperoxide (TP) receptor with SQ29.548 completely protected against LPS-induced AHR and VHR. Blockade of cyclooxygenase-2 (COX-2) abolished LPS-induced VHR but suppressed LPS-induced AHR only marginally. COX-2 messenger RNA was upregulated in LPS-treated lungs, and inhibition of transcription with actinomycin D or of protein biosynthesis with cycloheximide protected against LPS-induced VHR but not AHR. Pretreatment with the radical scavenger N-acetylcysteine partly protected against LPS-induced AHR. In addition, perfusion of mouse lungs with the isoprostane 8-epiprostaglandin F(2alpha) (8-epi-PGF(2alpha)), which may be formed as a consequence of oxidative stress in the lung, elicited AHR, which was completely blocked by SQ29.548. Enzyme immunoassay did not detect either 8-epi-PGF(2alpha )or thromboxane B(2) in perfusate samples. Our findings show that LPS induces AHR and VHR in mouse lungs via activation of the TP receptor. Although induction of VHR depends on COX-2 activity, AHR is largely mediated by a non-COX-derived TP agonist, which might be a product of radical-induced lipid peroxidation.
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PMID:Mechanisms of endotoxin-induced airway and pulmonary vascular hyperreactivity in mice. 1102 75

Neutrophils (PMNs) are implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). The role of the epithelium in the modulation of PMN migration within the lungs was examined. Epithelial integrity and PMN concentrations in the lung air spaces and lymph were measured in sheep anaesthetized with either halothane (1-2.5%) or intravenous pentobarbital (12+/-4 mg x kg(-1) x h(-1)). Ventilation with an aerosol containing 25 mg Escherichia Coli endotoxin (lipopolysaccharide; LPS) effected neutrophil recruitment to the air spaces. Lymphatic clearance of aerosolized 99mTc-DTPA provided an index of epithelial integrity. Three hours after the deposition of LPS, the lung lining fluid of sheep anaesthetized with halothane (n=7) had 4.9+/-3.2x10(6) PMN.mL(-1), but the lung lymph had almost no PMNs (3+/-8%). Sheep anaesthetized with pentobarbital (n=6) had fewer PMNs in the air spaces (2.4+/-1.2X10(6) mL(-1)) and more PMNs in the lung lymph (30+/-20%). Control sheep (n=5) that received no LPS had almost no PMNs in the airspaces or lung lymph, regardless of the anaesthesia. Three additional sheep that remained awake after receiving LPS also had no PMNs in the lung lymph. The PMN fraction in the lung lymph correlated well with the extra-alveolar epithelial permeability measured by lymphatic clearance of aerosolized diethylenetriamine penta-acetic acid (r=0.81, p<0.001). Aerosolized lipopolysaccharide recruits neutrophils into the lungs of sheep, but they appear to remain in the airspaces unless extra-alveolar permeability is increased by agents such as pentobarbital.
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PMID:Modulation by pentobarbital of neutrophil responses to inhaled E. coli endotoxin in sheep: role of lung epithelium. 1110 15

alpha 1-Acid glycoprotein (AAG), a highly negatively charged glycoprotein, well known for its capillary stabilizing effect, was tested in rat models of acute edematous pancreatitis, acute hemorrhagic-necrotizing pancreatitis, and acute respiratory distress syndrome (ARDS). In cerulein-elicited edematous pancreatitis AAG improved histological alterations at 200 mg/kg i.v. and plasma amylase activity at 1800 or 4200 mg/kg i.v. All other parameters (edema, plasma lipase) were not affected in a biologically relevant manner. In glycodeoxycholic acid-induced hemorrhagic-necrotizing pancreatitis AAG was without effect on parameters measured (plasma amylase, plasma lipase activity, histological scores) at 1800 or 4200 mg/kg i.v. At the extremely high dose of 1500 mg/kg i.v. plasma amylase and lipase levels were decreased. In lipopolysaccharide-mediated ARDS, AAG was tested at 50, 200 or 600 mg/kg i.v. AAG, but also the placebo formulation decreased the myeloperoxidase content in the bronchoalveolar lavage fluid. Histological alterations were improved by AAG, however, not by the placebo formulation. Lung water content was not significantly influenced by AAG, whereas Evans blue extravasation was significantly diminished by all three doses of AAG. It is concluded that the edematous pancreatitis is the first in vivo condition with increased extravascular fluid accumulation, in which AAG is not effective. Based on data presented here and literature data, there is evidence for a beneficial effect of AAG in acute lung injury.
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PMID:Effects of alpha 1-acid glycoprotein on acute pancreatitis and acute lung injury in rats. 1114 65

The effects of the administration of Escherichia coli endotoxin (lipopolysaccharide, LPS) into the airways of C57Bl/6 mice were studied. Neutrophil sequestration in the lungs and their enrichment, together with tumor necrosis factor (TNF)-alpha, in bronchoalveolar lavage fluid (BALF) were associated with bronchoconstriction and bronchopulmonary hyperreactivity (BHR) to methacholine and alveolocapillary dysfunction. Granulocyte depletion by the myelotoxic drug vinblastine failed to modify TNF-alpha production and prevented LPS-induced neutrophil recruitment to lungs and BALF, bronchoconstriction, and BHR. Neutrophils were again sequestered in the lungs when LPS was administered 4 to 5 d after vinblastine, whereas inhibition of their passage to BALF persisted. Under those conditions, bronchoconstriction and BHR by LPS also recovered, showing that these functional effects are independent from BALF neutrophil enrichment but require lung sequestration. Administration of granulocyte colony-stimulating factor after vinblastine counteracted its effects and allowed the recovery of lung neutrophil sequestration by LPS and a partial recovery of bronchoconstriction under conditions where neutrophils still failed to migrate to BALF. Dexamethasone (the phosphate salt and its free base) suppressed LPS-induced TNF-alpha generation in BALF and its neutrophil enrichment, whereas neutrophil lung sequestration, bronchoconstriction, BHR, and alveolocapillary dysfunction were marginally reduced and only so at low doses of dexamethasone, higher doses being inactive or aggravating. In situ neutrophil activation could account for LPS-induced bronchoconstriction and BHR, both of which are refractory to steroids and appear to be mediated by unrelated mechanisms, which may be relevant for acute respiratory distress syndrome, a condition for which LPS administration is used as a model.
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PMID:Airway administration of Escherichia coli endotoxin to mice induces glucocorticosteroid-resistant bronchoconstriction and vasopermeation. 1124 35

Recent clinical trials have shown that the survival of patients with acute respiratory distress syndrome (ARDS) is improved by ventilation with reduced volumes. These studies suggested that overinflation of the lungs causes overactivation of the immune system. The present study investigated the hypothesis that ventilation with increased tidal volumes results in early responses similar to those caused by stimulation with one of the major risk factors for ARDS: bacterial lipopolysaccharide (LPS). We therefore compared the effects of ventilation (-10 cm H2O or -25 cm H2O end-inspiratory pressure) and LPS (50 microg/ml) on nuclear factor (NF)-kappaB activation, chemokine release, and cytokine release in isolated perfused lungs obtained from BALB/C mice. We found that both LPS and ventilation with -25 cm H2O (overventilation; OV) caused translocation of NF-kappaB, which was abolished by pretreatment with the steroid dexamethasone. Furthermore, both treatments resulted in similar increases in perfusate levels of alpha-chemokines (macrophage inflammatory protein; [MIP]-2; KC), beta-chemokines (macrophage chemotactic protein-1; MIP-1alpha), and cytokines (tumor necrosis factor-alpha, interleukin-6), which were largely prevented by dexamethasone pretreatment. In LPS-resistant C3H/HeJ mice, only OV, and not LPS, caused translocation of NF-kappaB and release of MIP-2. We conclude that OV evokes early inflammatory responses similar to those evoked by LPS (i.e., NF-kappaB translocation and release of proinflammatory mediators). The NF-kappaB translocation elicited by OV appears to be independent of Toll-like receptor 4 and not due to LPS contamination introduced by the ventilator. Our data further suggest that steroids might be considered as a subsidiary treatment during artificial mechanical ventilation.
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PMID:Ventilation-induced chemokine and cytokine release is associated with activation of nuclear factor-kappaB and is blocked by steroids. 1125 8

Clinical studies have shown positive associations among sustained and intense inflammatory responses and the incidence of bacterial infections. Patients presenting with acute respiratory distress syndrome (ARDS) and high levels of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), and IL-6, have increased risk for developing nosocomial infections attributable to organisms such as Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter spp., compared to those patients with lower levels. Our previous in vitro studies have demonstrated that these bacterial strains exhibit enhanced growth extracellularly when supplemented with high concentrations of pure recombinant TNF-alpha, IL-1 beta, or IL-6. In addition, we have shown that the intracellular milieu of phagocytic cells that are exposed to supraoptimal concentrations of TNF-alpha, IL-1 beta, and IL-6 or lipopolysaccharide (LPS) favors survival and replication of ingested bacteria. Therefore, we hypothesized that under conditions of intense inflammation the host's micromilieu favors bacterial infections by exposing phagocytic cells to protracted high levels of inflammatory cytokines. Our clinical studies have shown that methylprednisolone is capable of reducing the levels of TNF-alpha, IL-1 beta, and IL-6 in ARDS patients. Hence, we designed a series of in vitro experiments to test whether human monocytic cells (U937 cells) that are activated with high concentrations of LPS, which upregulate the release of proinflammatory cytokines from these phagocytic cells, would effectively kill or restrict bacterial survival and replication after exposure to methylprednisolone. Fresh isolates of S. aureus, P. aeruginosa, and Acinetobacter were used in our studies. Our results indicate that, compared with the control, stimulation of U937 cells with 100-ng/ml, 1.0-microg/ml, 5.0-microg/ml, or 10.0-microg/ml concentrations of LPS enhanced the intracellular survival and replication of all three species of bacteria significantly (for all, P = 0.0001). Stimulation with < or =10.0 ng of LPS generally resulted in efficient killing of the ingested bacteria. Interestingly, when exposed to graded concentrations of methylprednisolone, U937 cells that had been stimulated with 10.0 microg of LPS were able to suppress bacterial replication efficiently in a concentration-dependent manner. Significant reduction in numbers of CFU was observed at > or =150 microg of methylprednisolone per ml (P values were 0.032, 0.008, and 0.009 for S. aureus, P. aeruginosa, and Acinetobacter, respectively). We have also shown that steady-state mRNA levels of TNF-alpha, IL-1 beta, and IL-6 in LPS-activated cells were reduced by treatment of such cells with methylprednisolone, in a concentration-dependent manner. The effective dose of methylprednisolone was 175 mg, a value that appeared to be independent of priming level of LPS and type of mRNA. We therefore postulate that a U-shaped relationship exists between the level of expression of TNF-alpha, IL-1 beta, and IL-6 within the phagocytic cells and their abilities to suppress active survival and replication of phagocytized bacteria.
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PMID:Effects of methylprednisolone on intracellular bacterial growth. 1168 57

Serum concentrations of catecholamines are high in patients with sepsis or acute respiratory distress syndrome (ARDS). Because chemokines mediate the recruitment of neutrophils into inflammatory sites, we addressed the question of whether dopamine (DA) is able to influence chemokine production in endothelial cells under basal and proinflammatory conditions. To this end, lung microvascular endothelial cells (LMVEC) were stimulated or not for 24 h with the bacterial toxins lipopolysaccharide (LPS) (1 microg/ml) or lipoteichonic acid (LTA) (10 microg/ml) in the presence or absence of various concentrations of DA (1-100 microg/ml). Whereas under basal and stimulatory conditions, the addition of DA to endothelial cells dose-dependently increased IL-8 production, the production of ENA-78 and Gro-alpha was significantly inhibited (P < 0.01). This effect could still be demonstrated when the cells were stimulated for up to 3 h with LPS before DA administration. Similar findings were detected for the mRNA expression of these chemokines. The influence of DA on chemokine production was not receptor mediated and could be prevented by antioxidants or radical scavengers. Moreover, addition of H(2)O(2) to endothelial cells gave results similar to those observed with DA stimulation, suggesting a pivotal role for reactive oxygen species in DA-mediated modulation of chemokine production in endothelial cells. Our data thus demonstrate that DA administration results in the induction of oxidative stress, with profound effects on endothelial chemokine production.
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PMID:Modulation of chemokine production in lung microvascular endothelial cells by dopamine is mediated via an oxidative mechanism. 1171 7

Intra-amniotic lipopolysaccharide (LPS) and cytokines may decrease respiratory distress syndrome (RDS) and increase chronic lung disease in the newborn. The aim was to identify the primary inflammatory mediators regulating the expression of surfactant proteins (SP) in explants from immature (22-day-old fetus) and mature (30-day term fetus and 2-day-old newborn) rabbits. In immature lung, interleukin (IL)-1alpha and IL-1beta upregulated the expression of SP-A and SP-B. These effects of IL-1 were diminished, and SP-C mRNA was suppressed additively in the presence of tumor necrosis factor (TNF)-alpha and either LPS or interferon (IFN)-gamma. LPS, TNF-alpha, or IFN-gamma had no effect alone. In explants from the term fetus and the newborn, LPS, IL-1alpha, and TNF-alpha additively suppressed the SPs. LPS acutely induced IL-1alpha in alveolar macrophages in mature lung but not in the immature lung. IFN-gamma that generally has low expression in intrauterine infection decreased the age dependence of the other agonists' effects on SPs. The present study serves to explain the variation of the pulmonary outcome after an inflammatory insult. We propose that IL-1 from extrapulmonary sources induces the SPs in premature lung and is responsible for the decreased risk of RDS in intra-amniotic infection.
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PMID:Regulation of surfactant proteins by LPS and proinflammatory cytokines in fetal and newborn lung. 1188 Mar 7

1. In acute respiratory distress syndrome (ARDS) induced by endotoxins, a high production of inflammatory mediators by microvascular lung endothelial cells (LMVEC) can be observed. Activation of cells by endotoxins may result in elevated secretion of phospholipase A(2) (sPLA(2)) which is thought to contribute to tissue damage. The present study was undertaken to investigate the role of sPLA(2) in chemokine production in human lung microvascular endothelial cells (LMVEC) stimulated with the endotoxins lipopolysaccharide (LPS) and lipoteichoic acid (LTA). In particular, we investigated the effects of sPLA(2) inhibitors, specifically, the extracellular PLA(2) inhibitors (ExPLIs), composed of N-derivatized phosphatidyl-ethanolamine linked to polymeric carriers, and LY311727, a specific inhibitor of non-pancreatic sPLA(2). 2. ExPLIs markedly inhibited LPS and LTA induced production and mRNA expression of the neutrophile attracting chemokines IL-8, Gro-alpha and ENA-78, as well as of the adhesion molecules ICAM-1 and E-selectin. Concomitantly, ExPLIs inhibited the LPS-induced activation of NF-kappaB by LPS but not its activation by TNF-alpha or IL-1. 3. Endotoxin mediated chemokine production in LMVEC seems not to involve PLA(2) activity, since LPS stimulation was not associated with activation of intracellular or secreted PLA(2). It therefore seems that the inhibitory effect of the ExPLIs was not due to their PLA(2) inhibiting capacity. This was supported by the finding that the LPS-induced chemokine production was not affected by the selective sPLA(2) inhibitor LY311727. 4. It is proposed that the ExPLIs may be considered a prototype of potent suppressors of specific endotoxin-induced inflammatory responses, with potential implications for the therapy of subsequent severe inflammation.
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PMID:Inhibition of LPS-induced chemokine production in human lung endothelial cells by lipid conjugates anchored to the membrane. 1193 6

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