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)

Adult respiratory distress syndrome (ARDS) is characterized by acute lung injury with a high mortality rate and yet its mechanism is poorly understood. Sepsis syndrome and acid aspiration are the most frequent causes of ARDS, leading to increased lung permeability, enhanced polymorphonuclear neutrophil (PMN) sequestration and respiratory failure. Using a murine model of acute lung injury induced by septic syndrome or acid aspiration, we investigated the role of cytosolic phospholipase A2 (cPLA2) in ARDS. We found that disruption of the gene encoding cPLA2 significantly reduced pulmonary edema, PMN sequestration and deterioration of gas exchange caused by lipopolysaccharide and zymosan administration. Acute lung injury induced by acid aspiration was similarly reduced in mice with a disrupted cpla2 gene. Our observations suggest that cPLA2 is a mediator of acute lung injury induced by sepsis syndrome or acid aspiration. Thus, the inhibition of cPLA2-initiated pathways may provide a therapeutic approach to acute lung injury, for which no pharmaceutical agents are currently effective.
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PMID:Acute lung injury by sepsis and acid aspiration: a key role for cytosolic phospholipase A2. 1088 Nov 66

1. The effect of the novel ET(A) receptor antagonist LBL 031 and other selective and mixed endothelin receptor antagonists on endothelin-1 (ET-1)-induced and lipopolysaccharide (LPS)-induced microvascular leakage was assessed in rat airways. 2. Intravenously administered ET-1 (1 nmole kg(-1)) or LPS (30 mg kg(-1)) caused a significant increase in microvascular leakage in rat airways when compared to vehicle treated animals. 3. Pre-treatment with the selective ET(A) receptor antagonists, LBL 031 or PD 156707, or the mixed ET(A/B) receptor antagonist, bosentan (each at 30 mg kg(-1)), reduced ET-1-induced leakage to baseline levels. ET-1-induced leakage was not reduced by pre-treatment with the ET(B) selective antagonist BQ 788 (3 mg kg(-1)). 4. Pre-treatment with the selective ET(A) receptor antagonist, LBL 031 (0.1 mg kg(-1)) or PD 156707 (10 mg kg(-1)), or the mixed ET(A/B) receptor antagonist, bosentan (30 mg kg(-1)), reduced LPS-induced leakage by 54, 48 and 59% respectively. LPS-induced leakage was not affected by pre-treatment with the ET(B) selective antagonist BQ 788 (3 mg kg(-1)). 5. The data suggests that ET-1-induced microvascular leakage in the rat airway is ET(A) receptor mediated and that part of the increase induced by LPS may be due to the actions of ET-1. Therefore, a potent ET(A) receptor selective antagonist, such as LBL 031, may provide a suitable treatment for inflammatory diseases of the airways, especially those involving LPS and having an exudative phase, such as the septic shock-induced adult respiratory distress syndrome.
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PMID:Effect of endothelin antagonists, including the novel ET(A) receptor antagonist LBL 031, on endothelin-1 and lipopolysaccharide-induced microvascular leakage in rat airways. 1108 20

To determine the possible contribution of apoptosis in the pathogenesis of acute lung injury (ALI), we investigated Fas antigen (Fas), Fas ligand (FasL), perforin, granzyme A, and granzyme B expressions in a murine model of ALI after intratracheal instillation of Escherichia coli lipopolysaccharide (LPS: 0.3-30 microg) into the left lung. Lung injury, examined by water-to-dry weight ratio and albumin leakage, demonstrated maximal epithelial injury 1 d after 30 microg LPS instillation. Expressions of the proapoptosis molecules' mRNA were dose-dependently up-regulated, with maximal expression in the early phase in the instilled lung and most apparent 1 d after LPS instillation. Negligible mRNA expression of proapoptosis molecules was observed in noninstilled lungs. The terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling (TUNEL) demonstrated positive signals in neutrophils and macrophages as well as in alveolar wall cells of the instilled lung 1 d after LPS instillation. Immunohistochemistry demonstrated that Fas was up-regulated in alveolar and inflammatory cells and FasL-positive inflammatory cells migrated into the air spaces in the LPS-instilled lung. Intratracheal administration of P2 antibody, which is an anti-Fas blocking antibody, attenuated the lung injury after 30 microg LPS instillation without attenuating mRNA expressions of proapoptosis molecules and neutrophil accumulation in the lung. In contrast, concanamycin A, which inhibits the function of perforin, did not alter the outcome after LPS instillation. These results indicate that the Fas/FasL system could be important in the pathogenesis of LPS-induced ALI, and proper regulation of the FasL/Fas system might be important for potential treatment of ARDS.
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PMID:Fas/FasL-dependent apoptosis of alveolar cells after lipopolysaccharide-induced lung injury in mice. 1125 36

Addition of nonionic polymers such as polyethylene glycol (PEG) and dextran ameliorates inactivation of Survanta by a variety of substances in vitro. Addition of polymers to Survanta also improves pulmonary function when used to treat rats with lung injury caused by instillation of human meconium. To find whether this approach is effective in lung injuries that more closely resemble adult respiratory distress syndrome (ARDS), we have compared the use of Survanta with Survanta + PEG in two additional models of lung injury caused by either lipopolysaccharide (LPS) or HCl in adult rats. Significant improvement of serial measures for arterial oxygenation and of postmortem pressure-volume measurements were found after treatment with Survanta + PEG compared with Survanta alone. PEG added to Survanta increased resistance to inactivation caused by tracheal fluid taken from animals injured with HCl. Other work suggests that PEG promotes surfactant aggregation, separates surfactant from surfactant inhibitors, and enhances access of surfactant to the gas-liquid interface. The addition of polymers to surfactants may also be useful in the treatment of lung injury where inactivation of surfactant has already occurred.
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PMID:Polyethylene glycol/surfactant mixtures improve lung function after HCl and endotoxin lung injuries. 1170 8

The tissue-fixed macrophage (Mphi) is a key cell in the coordination of the excessive systemic immunoinflammatory response underlying the adult respiratory distress syndrome (ARDS). Macrophage-generated reactive oxygen intermediates (ROIs) are involved in both tissue destruction via lipid peroxidation and in the activation of these inflammatory cells. It is unclear whether oxidant-induced activation involves an extracellular effect and membrane destabilization or occurs through intracellular alteration of the redox state and direct involvement as second messengers. In this study, we compare the differential effects of known intracellular vs. extracellular antioxidants on the Mphi response to endotoxin. Rabbit alveolar Mphi were obtained by bronchoalveolar lavage and exposed to either the extracellular antioxidants [vitamin C (VC) (10-1000 microM), Trolox (100-1000 microM, superoxide dismutase (SOD) (10-500 microM))] or the intracellular antioxidants [N-acetylcysteine (NAC) (0.1-10 mM) or butylated hydroxyanisole (BHA) (10-200 microM)] for 1 h. Cells were subsequently stimulated with lipopolysaccharide at 10 ng/mL. After 18 h, supernatants were analyzed for tumor necrosis factor (TNF) and F2 isoprostane (F2ISP) production and cellular monolayers for procoagulant activity (PCA). A dose response inhibition of both TNF and PCA production was demonstrated after both NAC and BHA pretreatment but not with VC, Trolox, or SOD. In addition, northern blots revealed inhibition of TNF mRNA production by both NAC and BHA. F2ISP, a marker of membrane lipid peroxidation, was inhibited by BHA and Trolox but not NAC, VC, or SOD. In conclusion, antioxidants that are incorporated intracellularly are expected to be beneficial in the treatment of excessive inflammatory responses through the interruption of redox dependent signal transduction pathways and subsequent modulation of the Mphi proinflammatory response.
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PMID:Intracellular antioxidant activity is necessary to modulate the macrophage response to endotoxin. 1209 35

Acute respiratory distress syndrome (ARDS) is an acute lung injury of high mortality rate, and sepsis syndrome is one of the most frequent causes of ARDS. Metabolites of arachidonic acid, including thromboxanes and leukotrienes, are proinflammatory mediators and potentially involved in the development of ARDS. A key enzyme for the production of these inflammatory mediators is cytosolic phospholipase A(2) (cPLA(2)). Recently, it has been reported that arachidonyl trifluoromethyl ketone (ATK) is a potent inhibitor of cPLA(2). In the present study, we hypothesized that pharmacological intervention of cPLA(2) could affect acute lung injury. To test this hypothesis, we examined the effects of ATK in a murine model of acute lung injury induced by septic syndrome. The treatment with ATK significantly attenuated lung injury, polymorphonuclear neutrophil sequestration, and deterioration of gas exchange caused by lipopolysaccharide and zymosan administration. The current observations suggest that pharmacological intervention of cPLA(2) could be a novel therapeutic approach to acute lung injury caused by sepsis syndrome.
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PMID:A potent inhibitor of cytosolic phospholipase A2, arachidonyl trifluoromethyl ketone, attenuates LPS-induced lung injury in mice. 1250 70

Acute respiratory distress syndrome (ARDS) is associated with altered plasma and lung iron chemistry. Iron can promote microbial virulence and catalyse pro-oxidant reactions, thereby contributing to the oxidative stress that characterises the syndrome. Therefore, the expression of ferritin and transferrin receptors (TfR) were sought in the lungs and hearts of rodents treated with lipopolysaccharide (LPS), and measurements of TfR and ferritin protein expression were taken from lung biopsy specimens from patients with ARDS and appropriate controls. TfR messenger ribonucleic acid (mRNA) was significantly upregulated in the lungs and significantly downregulated in the hearts of rats 4 h after LPS. Ferritin mRNA levels (light and heavy chains) remained unaltered. Protein TfR levels were significantly upregulated in lungs and downregulated in hearts 4 h post-LPS. Ferritin protein levels were significantly downregulated in lungs compared to baseline values but were unaltered in hearts. Nonhaem iron levels were increased in lungs and decreased in hearts, and iron-regulatory-protein activity increased in hearts but not lungs. TfR protein levels were significantly increased in lung biopsies from patients with ARDS compared to controls. Transferrin receptors are upregulated in rodent lungs during inflammation but are downregulated in the heart. Transferrin receptor protein levels were significantly increased in the lungs in clinical acute respiratory distress syndrome. These findings have implications for the pathogenesis of acute respiratory distress syndrome, especially in relation to the role of iron as a mediator of oxidative stress.
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PMID:Variable tissue expression of transferrin receptors: relevance to acute respiratory distress syndrome. 1295 70

Acute respiratory distress syndrome (ARDS) is a life-threatening ailment characterized by severe lung injury involving inflammatory cell recruitment to the lung, cytokine production, surfactant dysfunction, and up-regulation of nitric oxide synthase 2 (NOS2) resulting in nitric oxide (NO) production. We hypothesized that NO production from NOS2 expressed in lung parenchymal cells in a murine model of ARDS would correlate with abnormal surfactant function and reduced surfactant protein-B (SP-B) expression. Pulmonary responses to nebulized endotoxin (lipopolysaccharide, LPS) were evaluated in wild-type (WT) mice, NOS2 null (-/-) mice, and NOS2-chimeric animals derived from bone marrow transplantation. NOS2-/- animals exhibited significantly less physiologic lung dysfunction and loss of SP-B expression than did WT animals. However, lung neutrophil recruitment and bronchoalveolar lavage cytokine levels did not significantly differ between NOS2-/- and WT animals. Chimeric animals for NOS2 exhibited the phenotype of the recipient and therefore demonstrated that parenchymal production of NOS2 is critical for the development of LPS-induced lung injury. Furthermore, administration of NO donors, independent of cytokine stimulation, decreased SP-B promoter activity and mRNA expression in mouse lung epithelial cells. This study demonstrates that expression of NOS2 in lung epithelial cells is critical for the development of lung injury and mediates surfactant dysfunction independent of NOS2 inflammatory cell expression and cytokine production.
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PMID:Nitric oxide synthase-2 down-regulates surfactant protein-B expression and enhances endotoxin-induced lung injury in mice. 1520 61

In this paper, we show that plasma from patients with severe sepsis and septic shock but not normal plasma supports lipopolysaccharide (LPS) activation of epithelial cells expressing Toll-like receptor 4 (TLR4). Recombinant soluble myeloid differentiation protein-2 (MD-2) complemented normal plasma and allowed LPS activation of epithelial cells to levels measured with "septic" plasma, whereas soluble MD-2-depleted plasma lost its effects. The same "MD-2 activity" was found in urine from a patient with septic shock and in lung edema fluids from patients with adult respiratory distress syndrome (ARDS). Recombinant soluble MD-2 enabled LPS-dependent activation of epithelial cells bearing TLR4. LPS-binding protein (LBP) and soluble CD14 increased the sensitivity of TLR4-expressing epithelial cells to LPS but were not able to mediate LPS activation of these cells in the absence of soluble MD-2. An anti-MD-2 monoclonal antibody blocked LPS activation of TLR4-expressing cells only in the presence of septic plasma or septic urine. These results suggest that septic plasma containing soluble MD-2 leaking into the extravascular space supports LPS activation of TLR4-expressing epithelial cells. We therefore propose that soluble MD-2 is an important mediator of organ inflammation during sepsis.
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PMID:Soluble MD-2 activity in plasma from patients with severe sepsis and septic shock. 1532 61

Acute respiratory distress syndrome (ARDS) is characterized by an intense inflammatory response in the lung parenchyma. Recent studies suggest that excessive nitric oxide (NO) production mediated by inducible NO synthase (iNOS) in macrophages is partially involved in mediating acute lung injury in ARDS. On the other hand, osteopontin (OPN) is a cytokine which is capable of inhibiting NO production by suppressing iNOS mRNA expression in macrophages. In this study, we investigated the expression of OPN in the lungs of 10 patients with ARDS. In most patients, OPN is strongly expressed on alveolar macrophages. In addition, we produced a murine model for ARDS by intratracheal administration of lipopolysaccharide and investigated the expression of endogenous OPN and iNOS in the lungs of ARDS mice. Immunostaining demonstrated that in vivo OPN protein was coinduced with iNOS protein predominantly in the accumulating alveolar macrophages. OPN mRNA expression was also coinduced with iNOS mRNA, but was induced more slowly than iNOS mRNA in the lungs of ARDS mice. These results suggested that OPN, which may reduce NO production of macrophages by inhibiting iNOS expression, is significantly induced and expressed on alveolar macrophages in the lungs of ARDS. It is possible that OPN is partially involved in playing a protective role against excessive production of NO in ARDS.
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PMID:Osteopontin is strongly expressed by alveolar macrophages in the lungs of acute respiratory distress syndrome. 1552 56


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