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)

1. To evaluate the possible contribution of endothelin-1 (ET-1) to the pathophysiology of porcine septic shock, the non-peptide, mixed ET-receptor antagonist, bosentan (RO 47-0203) was administered (5 mg kg-1, i.v.) 30 min before infusion of lipopolysaccharide (LPS) (E. coli., serotype 0111:B4) (15 micrograms kg-1 h-1) and at 3.5 h of endotoxaemia in six anaesthetized and mechanically ventilated pigs. Six other pigs served as controls and received only LPS infusion. Pulmonary and systemic haemodynamics as well as splenic, renal and intestinal blood flows were measured continuously. Release and synthesis of ET-1 and Big ET-1 were also measured. 2. Only three of the six pigs in the control group survived 3 h of LPS infusion while in the bosentantreated group all six pigs were alive at that time. A biphasic increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR) was seen in control pigs. Pretreatment with bosentan did not influence the first peak but markedly attenuated the second, more prolonged increase in MPAP and PVR. The second dose of bosentan completely restored these parameters to pre-LPS levels. The LPS-induced changes in mean arterial blood pressure, heart rate and systemic vascular resistance were similar in both groups, while cardiac output (CO) was significantly higher in the bosentan-treated group. The second bosentan dose increased CO and splenic and intestinal blood flow without further lowering of blood pressure. 3. Bosentan caused an increase of the basal arterial plasma levels of ET-1-like immunoreactivity (LI), from 16.8 +/- 1.3 pM to 49.6 +/- 10.0 pM (n = 6, P < 0.01). However, the rate of the increase of ET-1 levels during the LPS infusion was not affected by bosentan. Repeated administration of bosentan during LPS infusion caused an additional increase of ET-1-LI levels. Neither the basal levels of Big ET-LI nor the LPS induced 8 fold increase in Big ET-LI were changed by bosentan. The level of preproET-1 mRNA in the lung was increased about 3 fold after 4.5 h of LPS treatment. This elevation was not influenced by bosentan. 4. From these studies using bosentan, a non-peptide, selective and mixed ET-receptor antagonist, we conclude that during LPS-induced shock bosentan can abolish the late phase pulmonary hypertension and improve cardiac output as well as increase blood flow to the splenic and intestinal vascular beds without causing a further decrease in mean arterial blood pressure. Further investigations in the clinical setting are needed to evaluate the use of ET-receptor antagonists, such as bosentan, in treatment of septic shock.
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PMID:Bosentan-improved cardiopulmonary vascular performance and increased plasma levels of endothelin-1 in porcine endotoxin shock. 876 86

Hypoxic pulmonary vasoconstriction (HPV) is an important mechanism for maintaining oxygenation, which may be altered by endotoxin. We determined that acute endotoxemia alters the HPV response secondary to changes in endothelium-derived vasoactive products. Rats were treated with Salmonella typhimurium lipopolysaccharide (LPS; 15 mg/kg i.p.) either 1 to 6 h before lung isolation and compared with control rats (no LPS). Additional 6-h LPS-treated and control rats were pretreated with either indomethacin (15 mg/kg i.p.), a cyclooxygenase inhibitor, or bosentan (10 mg/kg po), a nonselective endothelin-receptor antagonist. The rats lungs were isolated and challenged with 3% O2 for 10 min to elicit HPV responses before and after nitric oxide (NO) synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME; 100 microM). LPS (6 h) significantly increased the peak HPV responses by 108%. L-NAME had no significant effect in LPS-treated lungs but increased the peak HPV response in control lungs to levels equal to LPS-treated lungs. Bosentan increased the peak HPV response in all lungs, and indomethacin increased the peak HPV in LPS-treated lungs. The HPV response was sustained in control lungs at 10 min and in additional 20-min studies. In contrast, in LPS-treated lungs the HPV response faded after 10 min to levels equal to control, and in 20-min studies it faded by 82% to levels significantly less than in control lungs. The 10-min fade in LPS-treated lungs was attenuated by indomethacin (51%) and bosentan (80%) but not by L-NAME. In conclusion, acute endotoxemia with LPS increased the peak HPV response, but this effect was not sustained and by 20 min was nearly abolished. Inhibition of endogenous NO by LPS may explain the increased peak HPV response, but NO is not involved in the fade. The fade is at least partially due to increased vasodilating cyclooxygenase products and endothelins.
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PMID:Endotoxin alters hypoxic pulmonary vasoconstriction in isolated rat lungs. 888 69

To test whether endothelins are involved in the regulation of portal resistance after endotoxin pretreatment and whether their effects are modulated by nitric oxide (NO), rats received intraperitoneal injections of Escherichia coli lipopolysaccharide (LPS, 1 mg/kg body wt) or saline. Six and twenty-four hours later, livers were isolated and perfused. Analyses of portal pressure-flow (P-Q) relationships and epifluorescence microscopy were performed before and after administration of 1) the NO synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 10(-3) M), followed by L-arginine (2 x 10(-3) M), or 2) the endothelin ETA/ETB-receptor antagonist bosentan (2 x 10(-4) M), followed by L-NAME (10(-3) M). LPS pretreatment increased all measures of resistance, which included total portal resistance, zero flow, incremental resistance (slopes of P-Q relationship), and sinusoid resistance. L-NAME had no effect in sham controls but increased all measures of resistance at 6 h after LPS and increased total and incremental resistance 24 h after LPS. L-Arginine reversed these changes. Bosentan reduced total and sinusoid resistance slightly in control livers and caused substantial reductions in all measures of resistance at 6 and 24 h after LPS; these were partially reversed after L-NAME at 6 but not at 24 h. Our data support the hypothesis that a critical balance between endothelin-mediated vasoconstrictor influences and NO-mediated vasodilator influences controls portal resistance after endotoxin pretreatment.
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PMID:A time-dependent balance between endothelins and nitric oxide regulating portal resistance after endotoxin. 894 14

Endothelin-1, unlike the selective endothelin ETB receptor agonist sarafotoxin S6c, causes nociception in the rat when injected intraarticularly into the naive knee-joint. By using selective antagonists, the present study further characterizes the receptors underlying the articular nociceptive actions of endothelin-1, as well as the possible contribution of endogenous endothelins towards nociception induced by carrageenan or E. coli lipopolysaccharide (LPS) in this tissue. Nociception was evaluated by placing the animal for 1 min each hour on a revolving (3 rpm) cylinder and measuring the increase in time the hindpaw of the limb affected by the intra-articular (i.a.) injection of the nociceptive agent, failed to touch its metallic surface (i.e. paw elevation time, PET). In naive joints, endothelin-1 (120 pmol) increased the area under the PET curve (AUC 0-6 h, in arbitrary units) from 61+/-3 (control) to 156+/-12. This nociceptive effect was reduced by prior intravenous (i.v.) injection of the mixed ET(A)/ET(B)receptor antagonist bosentan (by 54 and 73% with 10 and 30 mg/kg) or i.a. administration of the selective ETA receptor antagonist BQ-123 (cyclo [D-Asp-Pro-D-Val-Leu]; by approximately/= 45% with 10 or 30 nmol), but was unaffected by the selective ET(B) receptor antagonist BQ-788 (N-cis-2,6-dimethyl-piperidinocarbonyl-L-gamma-methoxycarbonyl- tryptophanil-D-norleucine; 10 nmol). Prior joint challenge with carrageenan (300 microg) 72 h beforehand (i.e. priming) rendered the joint more sensitive to nociception induced by either endothelin-1 or sarafotoxin S6c (15, 30 and 60 pmol). Responses elicited by endothelin (30 pmol) in the primed joint were sensitive to inhibition by either BQ-123 or BQ-788 (each causing approximately/= 80% inhibition at 10 nmol). Priming also enhanced PET responses to carrageenan itself and to LPS (1 microg) markedly and persistently, increasing the area under the curve (AUC 0-12 h, in arbitrary units) from 241+/-19 to 409+/-50 and from 312+/-40 to 466+/-25, respectively (P < 0.05), without changing that measured following vehicle injection (from 121+/-3 to 117+/-4). Bosentan (up to 30 mg/kg, i.v.) failed to modify nociception caused by carrageenan or LPS in naive joints, by carrageenan in the primed joint, or control PET responses. LPS-induced nociception in the primed joint, however, was inhibited by 52 to 56% by bosentan (3 or 10 mg/kg) or 59% by local injection of the selective endothelin ET(B) receptor antagonist BQ-788 (10 nmol, i.a.), but was unaffected by the selective endothelin ETA receptor antagonist BQ-123. Thus, nociception induced by endothelin-1 in the naive joint is mediated largely via endothelin ETA receptors, whereas both ET(A)and ET(B) receptors contribute to its action in the carrageenan-primed joint. Furthermore, LPS-induced nociception in the primed joint is mediated to a large extent via endothelin release and activation of ET(B) receptors within the joint itself. These findings may be relevant to the etiology of pain underlying chronic arthritic disease in humans.
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PMID:Articular nociception induced by endothelin-1, carrageenan and LPS in naive and previously inflamed knee-joints in the rat: inhibition by endothelin receptor antagonists. 980 51

The fever induced by lipopolysaccharide (LPS) depends on both prostaglandin-dependent and -independent pathways. One of the prostaglandin-independent pathways is sequentially orchestrated by pre-formed pyrogenic factor derived from LPS-stimulated macrophages (PFPF), corticotrophin releasing factor (CRF), endothelin-1 (ET-1) and interleukin-1 (IL-1). As macrophage-inflammatory-protein (MIP)-1 alpha (synonym CCL3) also induces a prostaglandin independent fever, the aim of the present study was to investigate a possible participation of CCL3/MIP-1 alpha within the prostaglandin-independent pathway of LPS-induced fever which depends on PFPF, CRF and ET-1. Therefore, rats received intracerebroventricular (i.c.v.) pre-treatment with anti-CCL3 monoclonal antibody (1 and 5 ng) at 1 h and 15 min before injection of LPS (lipopolysaccharide from E. coli; 5, 50 or 100 microg kg(-1), i.v.) or CCL3/MIP-1 alpha (500 pg, i.c.v.). Both doses of anti-CCL3 did not change the basal temperature but abolished the fever induced by CCL3/MIP-1 alpha. When given at the higher dose, anti-CCL3 did not influence the fever induced by i.v. injection of different doses of LPS, or i.c.v. administration of PFPF (200 ng), CRF (3 microg) or ET-1 (1 pmol). Bosentan, a non-selective ET(A/B) receptors antagonist (10 microg kg(-1), i.v.), reduced the fever induced by LPS but not that induced by CCL3/MIP-1 alpha. In contrast, alpha-helical CRF(9-41) (a non-selective CRF R1/R2 receptor antagonist; 25 microg injected i.c.v.) reduced CCL3/MIP-1 alpha-induced fever. In conclusion, the present results indicate that: i) CCL3/MIP-1 alpha is not an endogenous mediator of LPS-induced fever; ii) it is even not involved in the prostaglandin-independent pathway of the LPS-fever cascade and iii) its pyrogenic activity depends on synthesis/release of CRF.
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PMID:CCL3/MIP-1 alpha is not involved in the LPS-induced fever and its pyrogenic activity depends on CRF. 1928 86

Nitric oxide (NO) induces vascular relaxation via cGMP in vascular smooth muscle (VSM) and is an important mediator of vascular tone during sepsis, as endothelial NO synthase (eNOS) may be upregulated during the early stages. Atrial natriuretic peptide (ANP) also stimulates cGMP via eNOS hence, this study aimed to investigate the role of NO in time-dependent altered vascular responses to ANP during the first 4h of exposure to bacterial lipopolysaccharide (LPS). We used male rat saphenous arteries [internal relaxed diameter 63-152 microm, n=48], mounted on a wire myograph and pre-constricted with phenylephrine. At 2h in the presence of LPS, there was increased relaxation to ANP in arteries exposed to LPS [16.3+/-2.4%, P<0.05]. However the response to ANP was not altered by the NOS inhibitor Nomega-nitro-l-arginine methyl ester (L-NAME, 10(-4)M) and following denudation (vessels without endothelium). At 4h there was no longer increased relaxation to ANP in the presence of LPS. Moreover the vasodilator response to ANP was significantly reduced following L-NAME or denudation [4.4+/-1.0% and 4.3+/-1.1% respectively, P<0.05]. However, the non-specific endothelin-1 (ET-1) receptor antagonist Bosentan [10(-5)M] increased dilatation in LPS exposed arteries at 1 and 2h, reaching significance at 4h [14.0+/-3.4%, P<0.05]. In summary, an endothelial and NO dependent mechanism is responsible for increased relaxation to ANP following 2h exposure to LPS. However after 4h an endothelial and NO independent process involving ET-1 is responsible for decreased relaxation to ANP. The enhanced response to ANP may exacerbate early systemic vasodilatation during early sepsis.
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PMID:Lipopolysaccharide alters vasodilation to atrial natriuretic peptide via nitric oxide and endothelin-1: time-dependent effects. 1973 54

Bacterial infections induce exacerbations in chronic lung diseases, e.g., chronic obstructive pulmonary disease (COPD), by enhancing airway inflammation. Exacerbations are frequently associated with right heart decompensation and accelerate disease progression. Endothelin receptor antagonists (ERAs) might have therapeutic potential as pulmonary vasodilators and anti-inflammatory agents, but utility in exacerbations of chronic lung diseases is unknown. We hypothesized that cytokine releases induced by lipopolysaccharide (LPS), the major bacterial trigger of inflammation, are reduced by ERAs in pulmonary vascular smooth muscle cells (PVSMCs). Ex vivo cultivated human PVSMCs were preincubated with the endothelin-A-receptor selective inhibitor ambrisentan, with the endothelin-B-receptor selective inhibitor BQ788 [sodium (2R)-2-{[(2S)-2-({[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl}amino)-4,4-dimethylpentanoyl][1-(methoxycarbonyl)-d-tryptophyl]amino}hexanoate], or with the dual blocker bosentan before stimulation with smooth LPS (S-LPS), rough LPS (Re-LPS), or a mixture of long and short forms (M-LPS). Expression of cytokines and LPS receptors (TLR4, CD14) were analyzed via enzyme-linked immunosorbent assay (ELISA) and/or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). All LPS forms induced interleukin (IL)-6-, IL-8-, and granulocyte macrophage-colony stimulating factor (GM-CSF) release. Bosentan and BQ788 inhibited M-LPS-induced release of all cytokines and soluble CD14 (sCD14) but not TLR4 expression. Ambrisentan blocked M-LPS-induced IL-6 release but not IL-8, GM-CSF, or LPS receptors. IL-8 release induced by S-LPS, which requires CD14 to activate TLR4, was blocked by bosentan and BQ788. IL-8 release induced by Re-LPS, which does not require CD14 to activate TLR4, was insensitive to both bosentan and BQ788. In conclusion, PVSMCs contribute to inflammation in bacteria-induced exacerbations of chronic lung diseases. Inhibition of the endothelin-B receptor suppresses cytokine release induced by long/smooth LPS attributable to sCD14 downregulation. ERAs, particularly when targeting the endothelin-B receptor, might have therapeutic utility in exacerbations of chronic lung diseases.
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PMID:Endothelin receptor antagonists attenuate the inflammatory response of human pulmonary vascular smooth muscle cells to bacterial endotoxin. 2372 Apr 57

Smoking-induced COPD is characterized by chronic airway inflammation, which becomes enhanced by bacterial infections resulting in accelerated disease progression called exacerbation. Alveolar macrophages (AM) release endothelin-1 (ET-1), IL-6, CCL-2 and MMP-9, all of which are linked to COPD pathogenesis and exacerbation. ET-1 signals via ETA- and ETB-receptors (ETAR, ETBR). This is blocked by endothelin receptor antagonists (ERAs), like bosentan, which targets both receptors, ETAR-selective ambrisentan and ETBR-specific BQ788. Therefore, ERAs could have anti-inflammatory potential, which might be useful in COPD and other inflammatory lung diseases. We hypothesized that ERAs suppress cytokine release from AM of smokers and COPD subjects induced by lipopolysaccharide (LPS), the most important immunogen of gram-negative bacteria. AM were isolated from the broncho-alveolar lavage (BAL) of n=29 subjects (11 non-smokers, 10 current smokers without COPD, 8 smokers with COPD), cultivated and stimulated with LPS in the presence or absence of ERAs. Cytokines were measured by ELISA. Endothelin receptor expression was investigated by RT-PCR and western blot. AM expressed ETAR and ETBR mRNA, but only ETBR protein was detected. LPS and ET-1 both induced IL-6, CCL-2 and MMP-9. LPS-induced IL-6 release was increased in COPD versus non-smokers and smokers. Bosentan, ambrisentan and BQ788 all partially reduced all cytokines without differences between cohorts. Specific ETBR inhibition was most effective. LPS induced ET-1, which was exclusively blocked by BQ788. In conclusion, LPS induces ET-1 release in AM, which in turn leads to CCL-2, IL-6 and MMP-9 expression rendering AM sensitive for ERAs. ERAs could have anti-inflammatory potential in smoking-induced COPD.
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PMID:Endothelin receptor-antagonists suppress lipopolysaccharide-induced cytokine release from alveolar macrophages of non-smokers, smokers and COPD subjects. 2652 51