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 The characterization of the B1 kinin receptor, and some mediators involved in the inflammatory response elicited by intrathoracic (i.t.) administration of des-Arg9-bradykinin (BK) in the mouse model of pleurisy, was investigated. 2 An i.t. injection of des-Arg9-BK (10-100 nmol per site), a selective B1 agonist, caused a significant and dose-related increase in the vascular permeability observed after 5 min, which peaked at 1 h, associated with an increase in cell influx, mainly neutrophils, and, to a lesser extent, mononuclear cell influx, peaking at 4 h and lasting for up to 48 h. The increase in fluid leakage caused by des-Arg9-BK was completely resolved 4 h after peptide injection. I.t. injection of Lys-des-Arg9-BK (30 nmol per site) caused a similar inflammatory response. 3 Both the exudation and the neutrophil influx elicited by i.t. injection of des-Arg9-BK were significantly antagonized (P<0.01) by an i.t. injection of the selective B1 antagonists des-Arg9-[Leu8]-BK (60 and 100 nmol per site) or des-Arg9-NPC 17731 (5 nmol per site), administered in association with des-Arg9-BK (P<0.01), or 30 and 60 min before the cellular peak, respectively. In contrast, an i.t. injection of the B2 bradykinin selective receptor antagonist Hoe 140 (30 nmol per site), at a dose which consistently antagonized bradykinin (10 nmol per site)-induced pleurisy, had no significant effect on des-Arg9-BK-induced pleurisy. 4 An i.t. injection of the selective tachykinin receptor antagonists (NK1) FK 888 (1 nmol per site), (NK2) SR 48968 (20 nmol per site) or (NK3) SR 142801 (10 nmol per site), administered 5 min before pleurisy induction, significantly antagonized neutrophil migration caused by i.t. injection of des-Arg9-BK. In addition, FK 888 and SR 142801, but not SR 48968, also prevented the influx of mononuclear cells in response to i.t. injection of des-Arg9-BK (P<0.01). However, the NK3 receptor antagonist SR 142801 (10 nmol per site) also significantly inhibited des-Arg9-BK-induced plasma extravasation. An i.t. injection of the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP8-37 (1 nmol per site), administered 5 min before pleurisy induction, inhibited des-Arg9-BK-induced plasma extravasation (P<0.01), without significantly affecting the total and differential cell migration. 5 The nitric oxide synthase inhibitors L-NOARG and L-NAME (1 pmol per site), administered 30 min beforehand, almost completely prevented des-Arg9-BK (i.t.)-induced neutrophil cell migration (P<0.01), and, to a lesser extent, mononuclear cell migration (P<0.01). The D-enantiomer D-NAME had no effect on des-Arg9-BK-induced pleurisy. At the same dose range, L-NOARG and L-NAME inhibited the total cell migration (P<0.01). L-NAME, but not L-NOARG caused significant inhibition of des-Arg9-BK-induced fluid leakage. Indomethacin (1 mg kg(-1), i.p.), administered 1 h before des-Arg9-BK (30 nmol per site), inhibited the mononuclear cell migration (P<0.05), but, surprisingly, increased the neutrophil migration at 4 h without interfering with plasma extravasation. The administration of terfenadine (50 mg kg(-1), i.p.), 30 min before des-Arg9-BK (30 nmol per site), did not interfere significantly with the total cell migration or with the plasma extravasation in the mouse pleurisy caused by i.t. injection of des-Arg9-BK. 6 Pretreatment of animals with the lipopolysaccharide of E. coli (LPS; 10 microg per animal, i.v.) for 24 h did not result in any significant change of the inflammatory response induced by i.t. injection of des-Arg9-BK compared with the saline treated group. However, the identical treatment of mice with LPS resulted in a marked enhancement of des-Arg9-BK induced paw oedema (P<0.01). 7 In conclusion, we have demonstrated that the inflammatory response induced by i.t. injection of desArg9-BK, in a murine model of pleurisy, is mediated by stimulation of constitutive B1 receptors. (These responses are largely mediated by release of neuropeptides such as substanceP or CGRP and also by NO, but products derived from cyclo-oxygenase pathway and histamine seem not to be involved. Therefore, these results further support the notion that the B1 kinin receptor has an important role in modulating inflammatory responses, and it is suggested that selective B1 antagonists may provide therapeutic benefit in the treatment of inflammatory and allergic conditions.
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PMID:Characterization of the receptor and the mechanisms underlying the inflammatory response induced by des-Arg9-BK in mouse pleurisy. 948 17

1. In this study the mechanisms of the acute vasodilator action of bacterial lipopolysaccharide (LPS) were investigated in the rat Langendorff perfused heart. 2. Infusion of LPS (5 microg ml(-1)) caused a rapid and sustained fall in coronary perfusion pressure (PP) of 59 +/- 4 mmHg (n = 12) and a biphasic increase in NO levels determined in the coronary effluent by chemiluminescent detection. Both the fall in PP and the increase in NO release were completely abolished (n = 3) by pretreatment of hearts with the NO synthase inhibitor L-NAME (50 microM). 3. LPS-induced vasodilatation was markedly attenuated to 5 +/- 4 mmHg (n 3) by pretreatment of hearts with the B2 kinin receptor antagonist Hoe-140 (100 nM). 4. Vasodilator responses to LPS were also blocked by brief pretreatment with mepacrine (0.5 microM, n = 3) or nordihydroguaiaretic acid (0.1 microM, n = 4) and markedly attenuated by WEB 2086 (3 microM, n = 4). 5. Thirty minutes pretreatment of hearts with dexamethasone (1 nM), but not progesterone (1 microM), significantly modified responses to LPS. The action of dexamethasone was time-dependent, having no effect when applied either simultaneously with or pre-perfused for 5 min before the administration of LPS but inhibiting the response to LPS by 91 +/- 1% (n = 4) when pre-perfused for 15 min. The inhibition caused by dexamethasone was blocked by 15 min pretreatment with the glucocorticoid receptor antagonist RU-486 (100 nM) or by 2 min pre-perfusion of a 1:200 dilution of LCPS1, a selective antilipocortin 1 (LC1) neutralizing antibody. 6. Treatment with the protein synthesis inhibitor, cycloheximide (10 microM, for 15 min) selectively blunted LPS-induced vasodilatation, reducing the latter to 3 +/- 5 mmHg (n = 3), while having no effect on vasodilator responses to either bradykinin or sodium nitroprusside. 7. These results indicate that LPS-induced vasodilatation in the rat heart is dependent on activation of kinin B2 receptors and synthesis of NO. In addition, phospholipase A2 (PLA2) is activated by LPS resulting in the release of platelet-activating factor (PAF) and lipoxygenase but not cyclo-oxygenase products. These effects are dependent on de novo synthesis of an intermediate protein which remains to be identified.
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PMID:Mechanisms of acute vasodilator response to bacterial lipopolysaccharide in the rat coronary microcirculation. 951 82

There is compelling evidence to indicate an anti-inflammatory action of Zn2+. Most inflammatory diseases are associated with an increase of the inducible form of nitric oxide (NO) synthase. Additionally, inflammatory mediators such as histamine or bradykinin stimulate the constitutive NO synthase. Thus, the present study was undertaken to investigate whether Zn2+ inhibits production of inducible NO synthase and/or constitutive NO synthase activity to produce NO. Lipopolysaccharide, 5 mg/kg i.v., administered to Zn2+-deficient (ZD) rats, rats supplemented with Zn2+ sulfate (ZG), 10 mg/kg s.c., or controls resulted in a significant reduction of their serum Zn2+. The levels of N(G)-nitro-L-arginine methylester (L-NAME)-sensitive cyclic GMP (cGMP) in aortas isolated from ZD or ZG were significantly lower than those obtained from control animals. Zinc (100-150 microM) produced a dose-dependent inhibition of lipopolysaccharide or interleukin-1beta-induced NO formation in isolated rat aortic smooth muscle cells. Compared to cyclohexamide or actinomycin-D, the time course of inhibition of NO formation by 150 microM Zn2+ did not suggest an effect of Zn2+ on inducible NO synthase protein synthesis. Moreover, Zn2+ (150 microM) significantly reduced the rate of conversion of [3H]arginine to [3H]citrulline in lung homogenates from lipopolysaccharide-treated rats. Incubation of rat aortic smooth muscle cells and bovine pulmonary artery endothelial cell co-cultures with Zn2+ (150 microM) caused a significant reduction in basal and bradykinin- or A-23187-induced formation of cGMP. Thus, our results indicate that Zn2+ is capable of inhibiting lipopolysaccharide- or interleukin-1beta-induced NO formation as well as NO formation by constitutive NO synthase basally or in response to bradykinin or A-23187, and may explain the reported anti-inflammatory activity of Zn2+.
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PMID:Zn2+ inhibits nitric oxide formation in response to lipopolysaccharides: implication in its anti-inflammatory activity. 954 48

To determine the existence of the kallikrein-kinin system in vascular wall, the expression of low-molecular-weight (LMW) kininogen, a precursor protein of kinins, was studied in mouse aortic smooth muscle in vivo or in cultured vascular smooth muscle cells (VSMC) derived from mouse aorta in vitro. Although LMW-kininogen mRNA was undetectable in aortic smooth muscle of untreated mice using either Northern blotting or reverse transcription-polymerase chain reactions (RT-PCR) followed by Southern blotting, administration of lipopolysaccharide (LPS; 1 mg/kg, i.v.) induced the expression of LMW-kininogen mRNA at levels detectable by RT-PCR within 12 h. Cultured VSMC not only expressed LMW-kininogen mRNA at levels easily detectable by RT-PCR, but also secreted LMW-kininogen-like protein that was immunoreactive to anti-mouse LMW-kininogen antibody. These results demonstrate that VSMC are a source of LMW-kininogen in the mouse, and suggest the presence of a local kallikrein-kinin system in vascular tissue. LPS-induced up-regulation of LMW-kininogen expression suggests a role for vascular LMW-kininogen in tissue trauma or inflammation.
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PMID:Expression of low-molecular-weight kininogen in mouse vascular smooth muscle cells. 970 66

1. The effect of L-arginine (L-Arg), the nitric oxide synthase (NOS) substrate, on the responses to prostaglandin F2alpha (PGF2alpha, 10 microM) and K+ (120 mM) in rat middle cerebral artery (MCA) segments was analysed. 2. PGF2alpha induced a stable contraction of 0.35+/-0.06 mN mm(-1); the subsequent addition of bradykinin (BK, 1 microM) produced a relaxation of 42+/-9% of the PGF2alpha-induced tone. K+ induced a response consisting of a rapid basal tone increase (1.42+/-0.16 mN mm(-1)) followed by a decrease to a stable phase (1.24+/-0.15 mN mm(-1)). 3. L-Arg (0.1 mM), but not D-Arg, decreased the basal tone and reduced the contraction to PGF2alpha in segments with and without endothelium. The contractile response to K+ was also reduced and not maintained in the presence of L-Arg. 4. The inhibitory effect of L-Arg on the PGF2alpha- and K+-induced contractions was completely reversed by the NOS inhibitor, NG-monomethyl-L-arginine (L-NMMA, 0.1 mM). 5. Pre-incubation of segments with dexamethasone (1 microM), to inhibit inducible NOS (iNOS), or with the antibiotic polymyxin B (10 microg ml(-1)) reduced the L-Arg inhibition, whereas it was increased by lipopolysaccharide (LPS, 100 ng ml(-1)), an inductor of iNOS. L-NMMA antagonized the effects of dexamethasone and LPS. 6. The present results suggest that L-Arg inhibition of the PGF2alpha- and K+-induced contractions in rat MCA is the result of NO synthesis by iNOS stimulation.
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PMID:The L-arginine inhibition of rat middle cerebral artery contractile responses is mediated by inducible nitric oxide synthase. 973 Feb 65

To identify the presence of a local kallikrein-kinin system in vascular wall, we have studied whether rat vascular smooth muscle cells (VSMC) express kininogen in vitro and in vivo. Western blots using anti-T-kininogen antibody revealed the presence of T-kininogen in conditioned medium of cultured VSMC. T-Kininogen secretion by VSMC was markedly enhanced by the addition of lipopolysaccharide (LPS), angiotensin II (AII) and phorbol 12-myristate 13-acetate (PMA) to the culture. Experiments using specific inhibitors for protein kinases and on the PMA-induced down-regulation of protein kinase C suggested that a protein kinase C-dependent or unidentified pathway is involved in AII or LPS action, respectively. The intravenous injection of LPS (0.5 mg/kg) resulted in an increase in T-kininogen mRNA levels in the vascular smooth muscle of rat aorta, peaking at 16 h. Polyacrylamide gel electrophoresis of cDNA products generated by reverse transcription-polymerase chain reaction (RT-PCR) from aortic mRNA using primers specific for either T- or low-molecular-weight kininogen revealed that rat vascular smooth muscle expressed T-kininogen gene but not low-molecular-weight kininogen gene, and that LPS exclusively stimulated T-kininogen expression. The mRNA for high-molecular-weight kininogen was undetectable in either aortic smooth muscle or cultured VSMC by means of RT-PCR analysis. RT-PCR using specific primers for rat tissue kallikrein genes showed that aortic smooth muscle expressed KLK1 (true kallikrein) mRNA, but not KLK10 (T-kininogenase) mRNA. These results demonstrated that rat VSMC are a source of T-kininogen but not of low-molecular-weight- or high-molecular-weight kininogen, in contrast to the expression of true kallikrein but not of T-kininogenase by these cells.
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PMID:Kininogen expression by rat vascular smooth muscle cells: stimulation by lipopolysaccharide and angiotensin II. 973 61

We evaluated the potential of A549 cells, an alveolar type II epithelial cell line, to release granulocyte colony-stimulating factor (G-CSF), in addition to interleukin (IL)-8 and leukotriene B4, as neutrophil chemotactic activity (NCA). Human recombinant IL-1beta stimulated A549 cells to release NCA in a time- and dose-dependent fashion. The released NCA was blocked by mouse anti-human G-CSF polyclonal antibody. Molecular-sieve column chromatography revealed that IL-1beta induced the release of a 19- to 20-kDa chemotactic mass that was inhibited by anti-human G-CSF antibody. IL-1beta stimulated the release of G-CSF in a dose-dependent fashion, but the time-dependent profile of G-CSF showed that the concentration of G-CSF declined after 48 h. Tumor necrosis factor (TNF)-alpha, Escherichia coli lipopolysaccharide (LPS), and bradykinin (BK) stimulated A549 cells to release NCA that was inhibited by anti-G-CSF antibody. The release of G-CSF in response to TNF-alpha, LPS, and BK was significantly increased. The similar concentrations of human recombinant G-CSF (10-1,000 pg/ml) as in the supernatant fluid induced neutrophil chemotaxis. G-CSF mRNA was expressed time and dose dependently at 4 h and declined after 4 h in response to IL-1beta as evaluated by RT-PCR. The expression of G-CSF mRNA was also observed by TNF-alpha, LPS, and BK stimulation. These data suggest that type II alveolar epithelial cells may produce G-CSF as NCA and may participate in the regulation of leukocyte extravasation.
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PMID:Alveolar type II-like cells release G-CSF as neutrophil chemotactic activity. 975

Bradykinin (BK) and related kinins are potent inflammatory mediators produced during acute and chronic inflammation. The effects of these kinins are mediated via the stimulation of either a B2 or a B1 receptor. The B1 receptor is not normally present but its expression can be induced within 4 h by a variety of noxious stimuli, specifically, gram-negative bacteria or bacterial lipopolysaccharide (LPS) given to healthy animals. This study compared the cardiovascular response of healthy pigs and pigs diagnosed with a pre-existing spontaneously acquired infection to BK, a B2 receptor agonist, and des-Arg9-BK, a B1 receptor agonist. Eighty-eight percent of the animals diagnosed with an established infection based on a standardized clinical evaluation demonstrated increased sensitivity and responsiveness to des-Arg9-BK but normal responsiveness to BK and acetylcholine. In contrast, only 15% of healthy animals showed elevated responses to des-Arg9-BK. The response to des-Arg9-BK and BK in each group was characterised as B1 and B2, respectively, using the selective B1 and B2 antagonists Lys0-Leu8-des-Arg9-BK and Hoe 140, respectively. This study demonstrates the existence and function of the B1 receptor in animals with a previously acquired infection. These observations lend validity to animal experiments with LPS infusion in order to model bacterial inflammation.
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PMID:B1 kinin receptor activity in pigs is associated with pre-existing infection. 977 78

Central inflammation is an integral component and contributor of the pathology of many debilitating diseases and has been shown to produce spontaneous pain and hyperalgesia. Recently, administration of lipopolysaccharide (LPS) into the lateral ventricle of rats was shown to elicit both thermal hyperalgesia and tactile allodynia [K. Walker, A. Dray, M. Perkins, Hyperalgesia in rats following intracerebroventricular administration of endotoxin: effect of bradykinin B1 and B2 receptor antagonist treatment, Pain 65 (1996) 211-219]. In this study, we have replicated the LPS model with some adaptations and correlated the nociceptive behaviors with an increased expression of activated macrophages in the central nervous system. We also examined the effects of priming on LPS-induced decreases in thermal nociceptive thresholds and mechanical response thresholds following either central or peripheral administration. Intracerebroventricular (i.c.v.) administration of LPS (0.2 microgram/rat) did not alter either thermal (hot plate) or mechanical (von Frey filaments) thresholds compared to baseline values in the first few hours after injection. However, priming rats by pretreating with i.c.v. LPS (0.2 microgram) 24 h prior to testing with i.c.v. LPS (0.2 microgram) produced significant mechanical allodynia and thermal hyperalgesia. The mechanical allodynia had an onset of 80 min after injection and a duration of 5 h. A similar time course was observed for thermal hyperalgesia, although its expression was less pronounced. Immunohistochemical studies indicated an increased expression of activated macrophages in the brain parenchyma of primed rats but not in unprimed rats. Intraperitoneal (i.p., 2 mg/kg) administration of LPS had no significant effect on either thermal or mechanical thresholds in the first few hours after injection; however, priming rats via i.p. (0.2 mg/kg) or i.c.v. (0.2 microgram) LPS produced a reduction in both thermal nociceptive thresholds and mechanical response thresholds in rats given a subsequent i.p. injection of LPS. This study demonstrates that priming is an effective protocol for the induction of central inflammation and increases the duration of these behaviors after i.c. v. administration.
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PMID:Priming enhances endotoxin-induced thermal hyperalgesia and mechanical allodynia in rats. 979 8

Bradykinin B1 receptor-mediated responses increase as a function of in vitro incubation in the human umbilical vein. When tissues were continuously treated with the protein synthesis inhibitor, cycloheximide, or with the protein trafficking inhibitor, brefeldin A, pEC50 and maximal response to the selective bradykinin B1 receptor agonist, des-Arg9-bradykinin, were significantly diminished. The anti-inflammatory steroid, dexamethasone, produced a rightward shift of the concentration-response curve to des-Arg9-bradykinin, without affecting the maximal response. Furthermore, lipopolysaccharide or recombinant human interleukin-1 beta potentiate the bradykinin B1-sensitized responses, showing a leftward shift of the concentration-response curve to des-Arg9-bradykinin, without modifying the maximal response. On the other hand, bradykinin B2 receptor-mediated responses were unaffected by continuous exposure to cycloheximide, dexamethasone or lipopolysaccharide. These results provide pharmacological evidence to support the view that the de novo synthesis of bradykinin B1 receptors is involved in the induction of vascular responses in the human umbilical vein. This up-regulation process seems to be selective for bradykinin B1 receptors. The inhibitory effect of dexamethasone and the potentiating actions of lipopolysaccharide and exogenous human recombinant interleukin-1 beta on des-Arg9-bradykinin-mediated responses, suggest the possible role of interleukin-1 beta in the bradykinin B1 receptor up-regulation phenomenon in human umbilical vein.
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PMID:Bradykinin B1 receptors in human umbilical vein: pharmacological evidence of up-regulation, and induction by interleukin-1 beta. 982 88


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