Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pathological increases in vascular leakage lead to edema and swelling, causing serious problems in brain tumors, in diabetic retinopathy, after strokes, during sepsis and also in inflammatory conditions such as rheumatoid arthritis and asthma. Although many agents and disease processes increase vascular leakage, no known agent specifically makes vessels resistant to leaking. Vascular endothelial growth factor (VEGF) and the angiopoietins function together during vascular development, with VEGF acting early during vessel formation, and angiopoietin-1 acting later during vessel remodeling, maturation and stabilization. Although VEGF was initially called vascular permeability factor, there has been less focus on its permeability actions and more effort devoted to its involvement in vessel growth and applications in ischemia and cancer. Recent transgenic approaches have confirmed the profound permeability effects of VEGF (refs. 12-14), and have shown that transgenic angiopoietin-1 acts reciprocally as an anti-permeability factor when provided chronically during vessel formation, although it also profoundly affects vascular morphology when thus delivered. To be useful clinically, angiopoietin-1 would have to inhibit leakage when acutely administered to adult vessels, and this action would have to be uncoupled from its profound angiogenic capabilities. Here we show that acute administration of angiopoietin-1 does indeed protect adult vasculature from leaking, countering the potentially lethal actions of VEGF and inflammatory agents.
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PMID:Angiopoietin-1 protects the adult vasculature against plasma leakage. 1074 56

Sepsis leads to a reduction in vascular tone and a loss of vasoconstriction in response to catecholamines. We propose that angiopoietin-1 (Ang-1), which is known to modulate vascular inflammation and nitric oxide (NO), could improve responsiveness to vasopressor agents during sepsis. Mesenteric arterioles (300-400 microm) from rats (n=19) were mounted in a pressurized myograph and incubated with lipopolysaccharide (LPS, 50 microg/mL) for up to 4 h to model sepsis. Vasoconstriction (mean+/-SD) to phenylephrine (10(-8)-10(-3) M) was reduced in the presence of LPS (4 h, pD2: 5.8+/-0.2 (controls, n=6), 1.4+/-2.2 (LPS, n=6); maximal constriction: 48.2+/-4.8% (controls), 2.6+/-5.8% (LPS), P<0.05). However, in the presence of Ang-1 (250 ng/mL) phenylephrine caused greater vasoconstriction compared to LPS alone (4 h, pD2: 4.5+/-2.1; maximal constriction: 12.6+/-4.0% (n=7), P<0.05). In conclusion, Ang-1 increases vasoconstriction to phenylephrine in the presence of LPS. During sepsis therefore, Ang-1 increases vascular reactivity and has the potential to increase blood pressure and decrease vasopressor requirements in vivo.
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PMID:Angiopoietin-1 increases arteriolar vasoconstriction to phenylephrine during sepsis. 1600 88

Angiopoietin-1 (Ang-1), a ligand of the endothelium-specific receptor Tie-2, inhibits permeability in the mature vasculature, but the mechanism remains unknown. Here we show that Ang-1 signals Rho family GTPases to organize the cytoskeleton into a junction-fortifying arrangement that enhances the permeability barrier function of the endothelium. Ang-1 phosphorylates Tie-2 and its downstream effector phosphatidylinositol 3-kinase. This induces activation of one endogenous GTPase, Rac1, and inhibition of another, RhoA. Loss of either part of this dual effect abrogates the cytoskeletal and anti-permeability actions of Ang-1, suggesting that coordinated GTPase regulation is necessary for the vessel-sealing effects of Ang-1. p190 RhoGAP, a GTPase regulatory protein, provides this coordinating function as it is phosphorylated by Ang-1 treatment, requires Rac1 activation, and is necessary for RhoA inhibition. Ang-1 prevents the cytoskeletal and pro-permeability effects of endotoxin but requires p190 RhoGAP to do so. Treatment with p190 RhoGAP small interfering RNA completely abolishes the ability of Ang-1 to rescue endotoxemia-induced pulmonary vascular leak and inflammation in mice. We conclude that Ang-1 prevents vascular permeability by regulating the endothelial cytoskeleton through coordinated and opposite effects on the Rho GTPases Rac1 and RhoA. By linking Rac1 activation and RhoA inhibition, p190 RhoGAP is critical to the protective effects of Ang-1 against endotoxin. These results provide mechanistic evidence that targeting the endothelium through Tie-2 may offer specific therapeutic strategies in life-threatening endotoxemic conditions such as sepsis and acute respiratory distress syndrome.
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PMID:Angiopoietin-1 requires p190 RhoGAP to protect against vascular leakage in vivo. 1756 1

Angiopoietins are ligands for Tie-2 receptors and play important roles in angiogenesis and inflammation. While angiopoietin-1 (Ang-1) inhibits inflammatory responses, angiopoietin-2 (Ang-2) promotes cytokine production and vascular leakage. In this study, we evaluated in vivo and in vitro effects of Escherichia coli lipopolysaccharides (LPS) on angiopoietin expression. Wild-type C57/BL6 mice were injected with saline (control) or E. coli LPS (20 mg/ml ip) and killed 6, 12, and 24 h later. The diaphragm, lung, and liver were excised and assayed for mRNA and protein expression of Ang-1, Ang-2, and Tie-2 protein and tyrosine phosphorylation. LPS injection elicited a severalfold rise in Ang-2 mRNA and protein levels in the three organs. By comparison, both Ang-1 and Tie-2 levels in the diaphragm, liver, and lung were significantly attenuated by LPS administration. In addition, Tie-2 tyrosine phosphorylation in the lung was significantly reduced in response to LPS injection. In vitro exposure to E. coli LPS elicited cell-specific changes in Ang-1 expression, with significant induction in Ang-1 expression being observed in cultured human epithelial cells, whereas significant attenuation of Ang-1 expression was observed in response to E. coli LPS exposure in primary human skeletal myoblasts. In both cell types, E. coli LPS elicited substantial induction of Ang-2 mRNA, a response that was mediated in part through NF-kappaB. We conclude that in vivo endotoxemia triggers functional inhibition of the Ang-1/Tie-2 receptor pathway by reducing Ang-1 and Tie-2 expression and inducing Ang-2 levels and that this response may contribute to enhanced vascular leakage in sepsis.
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PMID:Regulation of angiopoietin expression by bacterial lipopolysaccharide. 1831 Feb 25

Angiopoietin 2 (Ang2) was originally shown to be a competitive antagonist for Ang1 of the receptor tyrosine kinase Tie2 in endothelial cells (ECs). Since then, reports have conflicted on whether Ang2 is an agonist or antagonist of Tie2. Here we show that Ang2 functions as an agonist when Ang1 is absent but as a dose-dependent antagonist when Ang1 is present. Exogenous Ang2 activates Tie2 and the promigratory, prosurvival PI3K/Akt pathway in ECs but with less potency and lower affinity than exogenous Ang1. ECs produce Ang2 but not Ang1. This endogenous Ang2 maintains Tie2, phosphatidylinositol 3-kinase, and Akt activities, and it promotes EC survival, migration, and tube formation. However, when ECs are stimulated with Ang1 and Ang2, Ang2 dose-dependently inhibits Ang1-induced Tie2 phosphorylation, Akt activation, and EC survival. We conclude that Ang2 is both an agonist and an antagonist of Tie2. Although Ang2 is a weaker agonist than Ang1, endogenous Ang2 maintains a level of Tie2 activation that is critical to a spectrum of EC functions. These findings may reconcile disparate reports of Ang2's effect on Tie2, impact our understanding of endogenous receptor tyrosine kinase signal transduction mechanisms, and affect how Ang2 and Tie2 are targeted under conditions such as sepsis and cancer.
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PMID:Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium. 1922 73

During sepsis endothelial dysfunction is an important pathogenetic mechanism in acute kidney injury (AKI). Lipopolysaccharide (LPS)-induced endotoxemia is associated with renal hemodynamic changes such as alterations of renal blood flow (RBF), vascular resistance, and glomerular filtration rate. We used adenoviral delivery of an engineered variant of native angiopoietin-1 (COMP-angiopoietin-1) containing anti-inflammatory and anti-permeability functions, to determine if regulation of renal endothelial cell dysfunction may have a beneficial role in preventing AKI during LPS-induced endotoxemia in mice. This treatment prevented the endotoxin-induced decrease of RBF and mean arterial pressure while improving glomerular filtration rate. Treatment also mitigated the effects of LPS on renal intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 protein expression, the number of ER-HR3-positive macrophages that infiltrated the kidney, serum nitrate/nitrite levels, renal inducible nitric oxide synthase protein expression, the induction of tubular epithelial reactive oxygen and nitrogen species, and renal microvascular permeability. Our findings show that COMP-angiopoietin-1, an endothelium-oriented therapeutic agent, protects against AKI caused by endotoxemia.
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PMID:COMP-angiopoietin-1 decreases lipopolysaccharide-induced acute kidney injury. 1981 42

Activated protein C (APC) is an anticoagulant, approved as a treatment for severe sepsis, that can prevent apoptosis, inflammation, and vascular leakage. The aim of this study was to investigate whether APC protects endothelial barrier function through the angiopoietin (Ang)/Tie2 axis. APC significantly up-regulated gene and protein expression of Tie2 and Ang1 in a dose (0.01-10 microg/ml)- and time (0.5-24 h)-dependent manner in human umbilical vein endothelial cells (HUVECs). Interestingly, it markedly inhibited Ang2 with an IC(50) of approximately 0.1 microg/ml. HUVEC permeability, measured using Evans blue dye transfer, was significantly reduced in the presence of APC, and, in concordance, the tight junction associated protein zona occludens (ZO)-1 was up-regulated and localized peripherally around cells, compared with controls. Smooth muscle cell migration toward APC-stimulated HUVECs was elevated compared with unstimulated cells. Blocking antibodies and small interfering (si) RNA treatment, compared with isotype (IgG) or scrambled siRNA controls, showed that APC requires 3 receptors, the endothelial protein C receptor, protease-activated receptor 1, and Tie2 to perform all these barrier stabilization functions. In summary, this study demonstrates that APC has novel effects on the Ang/Tie2 axis, which enhance endothelial barrier function and are likely to contribute to its therapeutic effect in sepsis and other diseases associated with vascular leakage.-Minhas, N., Xue, M., Fukudome, K., Jackson, C. J. Activated protein C utilizes the angiopoietin/Tie2 axis to promote endothelial barrier function.
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PMID:Activated protein C utilizes the angiopoietin/Tie2 axis to promote endothelial barrier function. 1985 95

Capillary permeability is a tightly regulated feature of microcirculation in all organ beds; however, in sepsis this feature is fundamentally altered. We previously reported elevated levels of vascular endothelial growth factor and its receptor (fms-like tyrosine kinase-1) in patients with septic shock, then investigated two kinds of angiopoietins in those patients. An enzyme-linked immunoassay was used to measure serum angiopoietin-1 and -2 levels in 12 patients with septic shock who were treated by direct hemoperfusion with a polymyxin B-immobilized fiber column (DHP-PMX). The angiopoietin-1 level was lower in patients with septic shock (7.01 +/- 10.08 ng/mL) than in controls (28.24 +/- 11.61 ng/mL, P < 0.001), but the angiopoietin-2 level was higher in septic shock patients (40.83 +/- 30.13 ng/mL vs. 2.47 +/- 1.78 ng/mL, P < 0.001). Between seven survivors and five non-survivors there was no significant difference in angiopoietin-1 levels before DHP-PMX therapy. During DHP-PMX therapy, however, the angiopoietin-2 level was significantly decreased in survivors (31.52 +/- 26.15 ng/mL vs. 17.32 +/- 22.46 ng/mL, P = 0.035). Moreover, at the end of the therapy, the angiopoietin-1 level was significantly lower in non-survivors (1.14 +/- 1.30 ng/mL vs. 10.43 +/- 13.56 ng/mL, P = 0.042), but the angiopoietin-2 level in non-survivors was significantly higher (70.79 +/- 40.47 ng/mL vs. 17.32 +/- 22.46 ng/mL, P = 0.019). The angiopoietin-2 level may be associated with vascular permeability in septic patients, and angiopoietins may be suitable markers of disease severity and mortality.
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PMID:Angiopoietin balance in septic shock patients treated by direct hemoperfusion with polymyxin b-immobilized fiber. 1995 76

Acute lung injury (ALI) in sepsis is characterized by an increase in microvascular permeability, resulting in pulmonary edema. Several studies have suggested that angiopoietin-1 and -2 play a contributory role in the pathogenesis of ALI. Polymyxin B-immobilized fiber column hemoperfusion is effective for sepsis-induced ALI. We investigated the angiopoietin levels before and after direct hemoperfusion with polymyxin B-immobilized fiber column (PMX) therapy. Enzyme-linked immunoassay was used to measure the serum angiopoietin-1 and -2 levels in 25 patients with septic shock treated with PMX. Eleven of the 25 patients were diagnosed with ALI. There was a significant positive correlation between the angiopoietin-1 level and the PaO(2) /FiO(2) ratio, but there was a significant inverse correlation between the angiopoietin-2 level and the PaO(2) /FiO(2) ratio. The mean angiopoietin-1 level before PMX therapy in the ALI group was significantly lower and the mean angiopoietin-2 level was significantly higher than in the non-ALI group. The mean angiopoietin-1 level of the ALI patients in response to PMX therapy was increased during PMX therapy, but that of the non-ALI patients with newly occurring ALI showed a decreased angiopoietin-1 level. On the other hand, the mean angiopoietin-2 level of the responders was decreased during PMX therapy, but that of patients with newly occurring ALI showed an increased angiopoietin-2 level. This result suggested that each angiopoietin-1 and -2 level may play a role in the pathogenesis of ALI and that PMX therapy ameliorates the angiopoietin balance in patients with ALI in sepsis.
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PMID:Angiopoietin balance in septic shock patients with acute lung injury: effect of direct hemoperfusion with polymyxin B-immobilized fiber. 2188 68

Angiopoietin-1 is a Tie-2 receptor agonist that stabilizes vascular endothelium, promoting endothelial maturation and preventing capillary leak. Angiopoietin-2 is largely a competitive partial antagonist that is markedly elevated in humans and animal models of sepsis and other inflammatory states, directly disrupts the endothelial barrier, and has been correlated with end-organ dysfunction and death in sepsis. In the previous issue of Critical Care, Alfieri and colleagues used intravital microscopy to study the microvasculature in a murine model of sepsis. Treatment with a modified angiopoietin-1 molecule led to reversal of albumin vascular leak and improved blood flow to skeletal muscle, as well as a decrease in the levels of several inflammatory cytokines. Importantly, the angiopoietin-1 variant was administered 20 hours after initial lipopolysaccharide challenge. This study adds to the evidence that the angiopoietin/Tie-2 axis represents a modifiable pathway through which targeted therapy may be able to directly reverse part of the pathology of sepsis.
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PMID:Fixing the leak: targeting the vascular endothelium in sepsis. 2303 62


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