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. During the course of studies directed to determine the transport of Angiotensin II AT(2) receptors in the rat brain, we found that stab wounds to the brain revealed a binding site recognized by the AT(2) receptor ligand CGP42112 but not by Angiotensin II. 2. We localized this novel site to macrophages/microglia associated with physical or chemical injuries of the brain. 3. The non-Angiotensin II site was also highly localized to inflammatory lesions of peripheral arteries. 4. In rodent tissues, high binding expression was limited to the spleen and to circulating monocytes. A high-affinity binding site was also characterized in human monocytes. 5. Lack of affinity for many ligands binding to known macrophage receptors indicated the possibility that the non-Angiotensin II CGP42112 binding corresponds to a novel site.6. CGP42112 enhanced cell attachment to fibronectin and collagen and metalloproteinase-9 secretion from human monocytes incubated in serum-free medium but did not promote cytokine secretion. 7. When added in the presence of lipopolysaccharide, CGP42112 reduced the lipopolysaccharide-stimulated secretion of the pro-inflammatory cytokines TNF-alpha, IL-1, IL-1 beta, and IL-6, and increased protein kinase A. 8. Molecular modeling revealed that a CGP42112 derivative was selective for the novel macrophage site and did not recognize the Angiotensin II AT(2) receptor. 9. These results demonstrate that CGP42112, previously considered as a selective Angiotensin II AT(2) ligand, recognizes an additional non-Angiotensin II site different from AT(2) receptors. 10. Our observations indicate that CGP42112 or related molecules could be considered of interest as potential anti-inflammatory compounds.
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PMID:The discovery of a novel macrophage binding site. 1663 92

To elucidate roles of microvascular factors in the pathogenesis of renal complications during endotoxemia, that is characterized by renal vasoconstriction and systemic hypotension/generalized non-renal vasodilation, we profile the expression pattern and time-course of three key vaso-regulators, namely endothelin (ET)-1, nitric oxide (NO), and angiotensin II (Ang II). We hypothesize that disruption of the overall balance between vasodilatation and vasoconstriction in the kidney, during the early phase of sepsis, contribute to its (kidney) predisposition to acute renal failure. Adult male Wistar rats were rendered endotoxemic at different time points (1, 3, 6 and 10 h) by a single i.p. injection of lipopolysaccharide (LPS) (15 mg/kg) dissolved in saline. Control group was injected vehicle only (saline). Both systolic and diastolic blood pressures significantly decreased at different time points after LPS administration. Surprisingly, renal histopathological evaluation showed no remarkable changes in LPS-induced endotoxemia. However, overall, levels of the vaso-regulators and, where applicable, their respective receptors were upregulated: (1) plasma ET-1 increased 25-fold and peaked, as renal ET-1 mRNA, at 3 h; renal ET-1 protein and its receptors, ET type A (ET(A)) receptor (vasoconstrictive) and ET type B (ET(B)) receptor (vasodilatatory) increased in a time-dependent fashion, (2) Ang II increased by 53% compared to control, peaking at 6 h. However, while levels of Ang II type 1 (AT1) receptor increased over time after LPS injection, those of Ang II type 2 (AT2) receptor were downregulated, (3) data of NO system (NO-NOS), the key vasodilator, were the most intriguing. Whereas levels of renal NO increased time-dependently following LPS administration, with a 2240-fold increase in renal iNOS expression, levels of eNOS, were almost unchanged. In conclusion, the present study overall reveals intriguing and complex dynamics between levels of vasoconstrictors and vasodilators during the early phase of LPS-induced endotoxemia. These shifts in molecular expressions are likely triggered by compensatory mechanisms aimed at counteracting the undesirable and dominant effects of one group of vaso-regulatory moiety over the other.
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PMID:Time-dependent expression of renal vaso-regulatory molecules in LPS-induced endotoxemia in rat. 1672 27

Our present study aimed to characterize the effects of lipopolysaccharide (LPS) on the expression of the bradykinin B2-receptor in the mouse heart, which may have a role in cardiac depression during sepsis. We found that LPS induced the up-regulation of B2-receptor mRNA in the heart in vivo and in cultured cardiac myocytes in vitro. Like LPS, tumor necrosis factor-alpha (TNF-alpha) but not interleukin (IL)-1-beta, IL-6 or endothelin-1 stimulated B2-receptor expression in cultured myocytes. The effect of LPS on the expression of B2-receptor mRNA was also mimicked in cardiac myocytes by Ang II via Ang II type 1 (AT1-) receptor. Losartan, an AT1-receptor antagonist, inhibited about 50% of the LPS-induced up-regulation of B2-receptor mRNA in the heart in vivo and in cultured cardiac myocytes in vitro. Furthermore, the up-regulation of B2-receptor mRNA by either LPS or Ang II in cultured myocytes was abolished by anti-TNF-alpha antibody. These results suggest that the up-regulation of cardiac B2-receptor expression by LPS is mediated through TNF-alpha, which is produced in the myocardium by two different mechanisms in an AT1-receptor-dependent and independent manners, implying the role of the cardiac kallikrein-kinin system in the development of cardiac dysfunction during sepsis.
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PMID:The lipopolysaccharide-induced up-regulation of bradykinin B2-receptor in the mouse heart is mediated by tumor necrosis factor-alpha and angiotensin II. 1675 7

Angiotensin II and glucose share components of their intracellular redox signaling pathways in endothelial and inflammatory cells. We hypothesized that valsartan, an angiotensin II blocker, attenuates hyperglycemia-induced endothelial dysfunction and downregulates release of proinflammatory cytokines from leukocytes. A sustained hyperglycemic clamp (12 mmol/L) to induce endothelial dysfunction was performed in healthy volunteers before and after 4 weeks of treatment with 160 mg of valsartan. Brachial artery flow-mediated vasodilation (FMD), lipopolysaccharide-induced release of interleukin-6 and TNF-alpha from peripheral blood leukocytes ex vivo, and circulating proinflammatory cytokines were determined before and during the clamp. The hyperglycemic clamp induced a decrease in FMD from 9.2 +/- 0.8 (t = 0 hr) to 4.4+/- 0.5 (t = 2 hr), 3.8 +/- 0.5 (t = 4 hr), and 4.8 +/- 0.5% (t = 22 hr) during the clamp. Valsartan attenuated endothelial dysfunction [FMD 7.0 +/- 0.7 (t = 2 hr), 6.1 +/- 0.7 (t = 4 hr), 6.2 +/- 0.6% (t = 22 hr); P < 0.005] and decreased the release of interleukin-6 and TNF-alpha from leukocytes both before and during the clamp (P < 0.05). Valsartan improves hyperglycemia-induced endothelial dysfunction and reduces the cytokine response to an inflammatory stimulus. A pathophysiological link between the effects of hyperglycemia and the renin-angiotensin system on endothelium and peripheral blood leukocytes may underlie the beneficial effects of inhibitors of the renin-angiotensin system on cardiovascular outcome in patients with diabetes mellitus.
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PMID:Angiotensin II type 1 receptor blockade improves hyperglycemia-induced endothelial dysfunction and reduces proinflammatory cytokine release from leukocytes. 1726 57

Endotoxin [or lipopolysaccharide (LPS)] increases levels of superoxide in blood vessels and impairs vasomotor function. Angiotensin II plays an important role in the generation of superoxide in several disease states, including hypertension and heart failure. The goal of this study was to determine whether the activation of the renin-angiotensin system contributes to oxidative stress and endothelial dysfunction after endotoxin. We examined the effects of enalapril (an angiotensin-converting enzyme inhibitor) or L-158809 (an angiotensin receptor blocker) on increases of superoxide and vasomotor dysfunction in mice treated with LPS. C57BL/6 mice were treated with either enalapril (60 mg.kg(-1).day(-1)) or L-158809 (30 mg.kg(-1).day(-1)) for 4 days. After the third day, LPS (10-20 mg/kg) or vehicle was injected intraperitoneally, and one day later, vasomotor function of the aorta was examined in vitro. After precontraction with PGF(2alpha), the maximal responses to sodium nitroprusside were similar in the aorta from normal and LPS-treated mice. In contrast, the relaxation to acetylcholine was impaired after LPS (54 +/- 5% at 10(-5), mean +/- SE) compared with vessels treated with vehicle (88 +/- 1%; P < 0.05). Enalapril improved (P < 0.05) relaxation in response to acetylcholine to 81 +/- 6% after LPS. L-158809 also improved relaxation in response to acetylcholine to 77 +/- 4% after LPS. Superoxide (measured with lucigenin and hydroethidine) was increased (P < 0.05) in aorta after LPS, and levels were reduced (P < 0.05) following enalapril and L-158809. Thus, after LPS, enalapril and L-158809 reduce superoxide levels and improve relaxation to acetylcholine in the aorta. The findings suggest that activation of the renin-angiotensin system contributes importantly to oxidative stress and endothelial dysfunction after endotoxin.
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PMID:Role of angiotensin II in endothelial dysfunction induced by lipopolysaccharide in mice. 1796 76

We previously demonstrated that angiotensin II (Ang II) receptor signaling is involved in azoxymethane-induced mouse colon tumorigenesis. In order to clarify the role of Ang II in COX-2 expression in the intestinal epithelium, the receptor subtype-specific effect on COX-2 expression in a rat intestinal epithelial cell line (RIE-1) has been investigated. Ang II dose- and time-dependently increased the expression of COX-2, but not COX-1 mRNA and protein. This stimulation was completely blocked by the AT(1) receptor antagonist but not the AT(2) receptor antagonist. Ang II and lipopolysaccharide (LPS) additively induced COX-2 protein in RIE-1 cells, whereas the LPS-induced COX-2 expression was significantly attenuated by low concentrations of Ang II or the AT(2) agonistic peptide CGP-42112A only in AT(2) over-expressed cells. These data indicate that Ang II bi-directionally regulates COX-2 expression via both AT(1) and AT(2) receptors. Control of COX-2 expression through Ang II signaling may have significance in cytokine-induced COX-2 induction and colon tumorigenesis.
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PMID:Angiotensin II bi-directionally regulates cyclooxygenase-2 expression in intestinal epithelial cells. 1854 83

This study was aimed at investigating the effects of Angiotensin (Ang) II stimulation on T lymphocytes mRNA expression of angiotensinogen (AGTN), angiotensin-converting enzyme (ACE) and AT1-receptor (R) and on ACE activity and Ang II content. The effects of Ang II stimulus were studied in lipopolysaccharide (LPS)-stimulated or not stimulated lymphocytes. mRNA expression for interferon-gamma (INF-gamma) was also studied to investigate whether a link between lymphocyte RAS and immunological function might occur. mRNAs for AGTN, ACE and AT1-R were obtained from peripheral blood of 18 healthy subjects and were quantified by real time quantitative transcriptase-polymerase chain reaction (PCR). ACE activity was assayed in cell pellets and supernatants by measuring the hippuric acid formation by high performance liquid chromatography (HPLC) and Ang II cell content was measured by radioimmunoassay (RIA) after HPLC separation. All determination were performed under baseline conditions and after the addition of 10(e- 13) M Ang II to LPS-stimulated or unstimulated lymphocytes. Ang II caused a significant upregulation of T subset lymphocytes gene expression of ACE and AT1-R and of INF gamma, and a marked increase in ACE activity and cell Ang II concentration. AGTN gene was never expressed. All these effects were further enhanced in T lymphocytes presitmulated by LPS and completely inhibited by Irbesartan. Our findings strongly support the evidence of a positive Ang II driven autocrine loop that upregulates cell RAS of isolated lymphocytes and activates the immuno response. The immuno-potentiating effect of Ang II, specifically shown in T subset, can be deleterious when local RAS are disregulated as in cardiovascular atherosclerotic disease.
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PMID:Angiotensin II upregulates renin-angiotensin system in human isolated T lymphocytes. 1872 52

Angiotensin II (Ang II) plays an important role in inflammatory process. Acute lung injury (ALI), an inflammatory disorder of the lung, is commonly associated with endotoxemia; however, the mechanism that endotoxin (lipopolysaccharide, LPS) induces the inflammatory response in ALI is not well defined. Here, we showed, in LPS-induced ALI rat model, that Ang II and Ang II type 1 (AT(1)) receptor were significantly increased in lung tissues, compared with those in controls. Meanwhile, nuclear factor (NF)-kappaB-DNA-binding activity, tumor necrosis factor (TNF)-alpha mRNA, and pneumocytic apoptosis were significantly increased. Moreover, pretreatment of rats with losartan, an antagonist of AT(1) receptor for Ang II, improved the inflammation, reduced the elevation of Ang II and AT(1) receptor, and inhibited NF-kappaB-DNA-binding activity, expression of TNF-alpha mRNA, and pneumocytic apoptosis. The data indicate that Ang II may mediate the inflammatory process in LPS-induced ALI through AT(1) receptor, which can be blocked by losartan.
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PMID:Losartan, an antagonist of AT1 receptor for angiotensin II, attenuates lipopolysaccharide-induced acute lung injury in rat. 1894 Jan 80

In addition to regulating blood pressure, angiotensin II (Ang II) exerts powerful pro-inflammatory effects in hypertension through stimulation of its AT(1) receptors, most clearly demonstrated in peripheral arteries and in the cerebral vasculature. Administration of Ang II receptor blockers (ARBs) decreases hypertension-related vascular inflammation in peripheral organs. In rodent models of genetic hypertension, ARBs reverse the inflammation in the cerebral microcirculation. We hypothesized that ARBs could be effective in inflammatory conditions beyond hypertension. Our more recent studies, summarized here, indicate that this is indeed the case. We used the model of systemic administration of the bacterial endotoxin lipopolysaccharide (LPS). LPS produces a robust initial inflammatory reaction, the innate immune response, in peripheral organs and in the brain. Pretreatment with the ARB candesartan significantly diminishes the response to LPS, including reduction of pro-inflammatory cytokine release to the general circulation and decreased production and release of the pro-inflammatory adrenal hormone aldosterone. In addition, the ARB very significantly decreased the LPS-induced gene expression of pro-inflammatory cytokines and microglia activation in the brain. Our results demonstrate that AT(1) receptor activity is essential for the unrestricted development of full-scale innate immune response in the periphery and in the brain. ARBs, due to their immune response-limiting properties, may be considered as therapeutically useful in a number of inflammatory diseases of the peripheral organs and the brain.
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PMID:Anti-inflammatory effects of angiotensin receptor blockers in the brain and the periphery. 1925 5

Systemic lipopolysaccharide (LPS) administration induces an innate immune response and stimulates the hypothalamic-pituitary-adrenal axis. We studied Angiotensin II AT(1) receptor participation in the LPS effects with focus on the pituitary gland. LPS (50 microg/kg, i.p.) enhanced, 3h after administration, gene expression of pituitary CD14 and that of Angiotensin II AT(1A) receptors in pituitary and hypothalamic paraventricular nucleus (PVN); stimulated ACTH and corticosterone release; decreased pituitary CRF(1) receptor mRNA and increased all plasma and pituitary pro-inflammatory factors studied. The AT(1) receptor blocker (ARB) candesartan (1mg/kg/day, s.c. daily for 3 days before LPS) blocked pituitary and PVN AT(1) receptors, inhibited LPS-induced ACTH but not corticosterone secretion and decreased LPS-induced release of TNF-alpha, IL-1beta and IL-6 to the circulation. The ARB reduced LPS-induced pituitary gene expression of IL-6, LIF, iNOS, COX-2 and IkappaB-alpha; and prevented LPS-induced increase of nNOS/eNOS activity. The ARB did not affect LPS-induced TNF-alpha and IL-1beta gene expression, IL-6 or IL-1beta protein content or LPS-induced decrease of CRF(1) receptors. When administered alone, the ARB increased basal plasma corticosterone levels and basal PGE(2) mRNA in pituitary. Our results demonstrate that the pituitary gland is a target for systemically administered LPS. AT(1) receptor activity is necessary for the complete pituitary response to LPS and is limited to specific pro-inflammatory pathways. There is a complementary and complex influence of the PVN and circulating cytokines on the initial pituitary response to LPS. Our findings support the proposal that ARBs may be considered for the treatment of inflammatory conditions.
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PMID:In vivo Angiotensin II AT1 receptor blockade selectively inhibits LPS-induced innate immune response and ACTH release in rat pituitary gland. 1942 76


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