Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objectives of this study were to determine 1) the changes in endothelial cell adhesion molecule expression that occur in a clinically relevant model of sepsis and 2) the dependence of these changes on endotoxin [lipopolysaccharide (LPS)]. The dual radiolabeled monoclonal antibody technique was used to quantify the expression of E- and P-selectin in LPS-sensitive (C3HeB/FeJ) and LPS-insensitive (C3H/HeJ) mice that were subjected to acute peritonitis by cecal ligation and perforation (CLP). At 6 h after CLP, the expression of both E- and P-selectin was increased in the gut (mesentery, pancreas, and small and large bowel) compared with the sham-operated and/or control animals, with a more marked response noted in LPS-insensitive mice. The lung also exhibited an increased P-selectin expression in both mouse strains. An accumulation of granulocytes, assessed using tissue myeloperoxidase activity, was noted in the lung and intestine of LPS-sensitive but not LPS-insensitive mice exposed to CLP. These results indicate that the CLP model of sepsis is associated with an upregulation of endothelial selectins in the gut vasculature and that enteric LPS does not contribute to this endothelial cell activation response.
 ...
PMID:Role of endotoxin in the expression of endothelial selectins after cecal ligation and perforation. 1080 Dec 80

Platelets and leukocytes are thought to play a leading role in the pathogenesis of many inflammatory conditions. To recruit flowing blood cells to the inflammatory region, it would be necessary for them to interact with vascular endothelial cells. Recently, many reports have indicated the resistance of spontaneous hypertensive rats (SHR) to endotoxic sepsis. Their resistance might be derived from suppressed interaction between these blood cells and endothelial cells. Therefore, SHR and age-matched Wistar-Kyoto rats (WKY) were induced with endotoxic sepsis by intravenous injection of lipopolysaccharide (LPS). At 4, 12, 24, and 48 hours after induction, leukocyte-endothelial interactions in the retina were evaluated in vivo with acridine orange digital fluorography. Fluorescently labeled platelets were also injected to investigate platelet-endothelial interactions in the retina in endotoxic sepsis. Leukocyte rolling in SHR after LPS injection was significantly suppressed; the maximum number of rolling leukocytes was reduced by 80.1% at 12 hours after LPS injection in SHR compared with WKY. Subsequent leukocyte infiltration into the vitreous cavity was significantly inhibited in SHR. Furthermore, platelet-endothelial interactions in the retina were also suppressed in SHR treated with LPS. The maximum numbers of rolling and adherent platelets were reduced by 59.5% and 62.6%, respectively, in SHR compared with WKY. In both strains, leukocyte- and platelet-endothelial interactions were substantially inhibited by the blocking of P-selectin. These suppressed interactions could contribute to the reduction of leukocyte- and platelet-mediated tissue injury in endotoxic sepsis in SHR, resulting in their resistance to endotoxemia.
 ...
PMID:Interactions between blood cells and retinal endothelium in endotoxic sepsis. 1094 86

In vitro, nitric oxide (NO) decreases leukocyte adhesion to endothelium by attenuating endothelial adhesion molecule expression. In vivo, lipopolysaccharide-induced leukocyte rolling and adhesion was greater in inducible NO synthase (iNOS)-/- mice than in wild-type mice. The objective of this study was to assess E- and P-selectin expression in the microvasculature of iNOS-/- and wild-type mice subjected to acute peritonitis by cecal ligation and perforation (CLP). E- and P-selectin expression were increased in various organs within the peritoneum of wild-type animals after CLP. This CLP-induced upregulation of E- and P-selectin was substantially reduced in iNOS-/- mice. Tissue myeloperoxidase (MPO) activity was increased to a greater extent in the gut of wild-type than in iNOS-/- mice subjected to CLP. In the lung, the reduced expression of E-selectin in iNOS-/- mice was not associated with a decrease in MPO. Our findings indicate that NO derived from iNOS plays an important role in sepsis-induced increase in selectin expression in the systemic and pulmonary circulation. However, in iNOS-/- mice, sepsis-induced leukocyte accumulation is affected in the gut but not in the lungs.
 ...
PMID:Endothelial E- and P-selectin expression in iNOS- deficient mice exposed to polymicrobial sepsis. 1120 53

Platelet-derived microparticles (PMPs) are released from platelets through the platelet activation by high shear stress, collagen, or calcium ionophore (A23187). PMPs are observed in patients with acute myocardial infarction, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, heparin-induced thrombocytopenia and other thrombotic disorders, but the importance of circulating PMPs in the pathogenesis of these diseases is still debated. Numbers of PMPs are usually determined by flowcytometry (FCM), but easier and reproducible PMP assay systems are needed. To develop a better ELISA for PMPs, we used antibodies against the platelet antigens anti-GPIb (NNKY5-5), anti-GPIIb/IIIa (NNKY2-11, anti-CD41), anti-GPIX (KMP-9), and anti-CD9 (NNKY1-19). PMPs were detected with all combinations of these antibodies, but the ELISA having the highest and most specific absorbance was obtained with a combination of KMP-9 (capture antibody) and NNKY5-5 (detecting antibody). PMPs in blood samples were measured by ELISA and FCM. ELISA correlated with PMPs quantitated by FCM. By shaking ELISA plates during incubation, nonspecific binding of platelets was eliminated. The level of PMPs was not increased in diabetes mellitus, thrombotic thrombocytopenic purpura, antiphospholipid syndrome, or sepsis. The concentration of PMP was elevated in hemolytic uremic syndrome. Activated PMPs were absorbed to 0.8 microm filter, but circulating PMPs were not absorbed. These results suggest that activated PMPs are likely to adhere to leukocytes or endothelial cells at the activation site and that the circulating form of PMPs are likely to be a residue of activated PMPs. To detect only the activated form of PMPs, a new ELISA needs to be developed, and it will likely use a combination of antibodies that detect platelet activation markers such as P-selectin (CD62P) or activated GPIIb/IIIa.
 ...
PMID:Development and assessment of enzyme immunoassay for platelet-derived microparticles. 1124 56

P-selectin is a major component in the early interaction between platelets, endothelial cells, and inflammatory cells in the initial phases of the innate immune response. The major ligand for P-selectin is P-selectin glycoprotein ligand-1 (PSGL-1) and this ligand is expressed on the surface of monocyte, lymphocyte, and neutrophil membranes. A truncated form of recombinant human P-selectin glycoprotein ligand-1 has been covalently linked to immunoglobulin G (rPSGL-Ig) and this fusion peptide functions as a competitive inhibitor of PSGL-1. As an inhibitor of neutrophil-endothelial cell adherence, rPSGL-Ig is in early clinical development for the treatment of ischemia reperfusion injury. To determine the potential for deleterious effects from inhibition in P-selectin-mediated neutrophil attachment in the presence of bacterial infection, the effects of therapeutic doses of rPSGL-Ig were tested in three standard laboratory sepsis models. The experimental models included: the murine systemic Listeria monocytogenes infection model, the Pseudomonas aeruginosa bacteremia model in neutropenic rats, and the cecal ligation and puncture (CLP)-induced peritonitis model in rats. Recombinant human PSGL-Ig had no adverse effects on mortality or immune clearance in systemic bacterial infection in any of the three infection models. The PSGL-1 inhibitor did significantly decrease local neutrophil infiltration and bacterial clearance in the peritoneum following CLP, but this did not increase the systemic levels of proinflammatory cytokines, the quantitative levels of bacteremia, or the overall mortality rate following CLP. The results indicate that rPSGL-Ig did not exacerbate infection in these experimental sepsis models.
 ...
PMID:Evaluation of the safety of recombinant P-selectin glycoprotein ligand-immunoglobulin G fusion protein in experimental models of localized and systemic infection. 1130 27

Sepsis, resistant to therapy, results in the development of septic (endotoxin) shock. The latter is caused by the endotoxins of different Gram-negative bacteria. Endotoxin (bacterial lipopdisacharide--LPS) interacts with cells through specific membrane or plasma soluble endotoxin receptors (sCD14, mlD14, LBP, CD13/CD14, CD16, CD116/CD18, L-selectin, etc.). Endotoxin interaction with the mCD14 receptor of the monocytes, macrophages and the neutrophils results in the production of a number of proinflammatory cytokines--tumor necrosis factor alpha (TNF alpha), interleukines 1 and 6 (IL-1 and IL-6, etc), antiinflammatory cytokines--interleukines 10 and 12 (IL-10 and IL-12), cell adhesion molecules (P-selectin, E-selectin, ICAM-1, VCAM-1, etc.) and inducible enzymes: inducible NO synthase (iNOS), inducible phospholipase A2 (cPL-A2), inducible cyclooxygenase (COX-2). All pathologic processes in the structure and function of human body during endotoxin shock are a result of the disbalance of a number of mediators with a proinflammatory and antiinflammatory effects.
 ...
PMID:[The role of bacterial endotoxins, receptors and cytokines in the pathogenesis of septic (endotoxin) shock]. 1168 28

Leukocyte interactions with vascular endothelium are an initial step for leukocyte entry into infectious foci where endothelial selectins may play a key role. Infiltrating leukocyte is essential for bacterial clearance, suggesting that endothelial selectins would be important in host defense against microorganisms. To address this, E-, P-, and E/P-selectin-deficient mice (E(-/-), P(-/-), E/P(-/-)) and wild-type (WT) mice underwent cecal ligation and puncture (CLP). Neither leukocyte infiltration nor bacterial load in the peritoneum was altered in E(-/-), P(-/-), and E/P(-/-) mice compared to WT mice. However, E(-/-), P(-/-), and E/P(-/-) mice were resistant to the lethality induced by CLP. At the mechanistic level, E(-/-), P(-/-), and E/P(-/-) mice did not develop renal dysfunction, a possible cause of death during sepsis. The serum level of interleukin-13 in E(-/-), P(-/-), and E/P(-/-) mice that had undergone CLP was higher than that in WT mice, whereas levels of macrophage inflammatory protein-2, KC in serum, and KC in kidney were lower than those in WT mice. These experiments demonstrate that endothelial selectin-mediated leukocyte rolling is not required for leukocyte entry in septic peritonitis and that endothelial selectins may affect mice survival during sepsis by influencing the cytokine profiles.
 ...
PMID:Mice genetically lacking endothelial selectins are resistant to the lethality in septic peritonitis. 1178 25

The effect of Staphylococcus aureus alpha toxin (alpha-toxin) on selectin-mediated neutrophil adhesion was investigated in polymorphonuclear leukocyte- (PMN) induced vasocontraction and endothelial dysfunction. Adherence of human PMNs to rat aortic endothelium increased significantly following stimulation of the endothelium with alpha-toxin (0.1, 0.5, and 1 microg/mL). This effect could be significantly attenuated by monoclonal antibodies directed against P-selectin or fucoidin, a carbohydrate known to block selectins. Unstimulated human PMNs (10(6)cells/mL) were added to organ chambers containing rat aortic rings stimulated with alpha-toxin (0.5 microg/mL). PMNs elicited a significant vasocontraction in alpha-toxin-stimulated, but not in control aortic, rings (142+/-12 mg versus 12+/-4 mg, P < 0.05). This PMN-induced vasocontraction was virtually blunted by pretreatment with MAb directed against P-selectin or fucoidin (P < 0.05). Endothelial function as assessed by endothelium-dependent vasorelaxation to acetylcholine was substantially inhibited after induction of PMN-induced vasocontraction in alpha-toxin-stimulated aortic rings. This endothelial dysfunction was reduced by P-selectin MAb or fucoidin. In contrast, endothelium-independent relaxation to sodium nitrite was not altered by PMN incubation, indicating that vascular smooth muscle function was unaffected. Thus, PMN-endothelial interaction following S. aureus a-toxin activation of the vascular endothelium is at least, in part, mediated by selectins. As a consequence, PMN-induced vasocontraction and endothelial dysfunction occur. Such mechanisms may be involved in microcirculation abnormalities encountered in sepsis or septic shock due to S. aureus infection.
 ...
PMID:Staphylococcus aureus alpha toxin mediates polymorphonuclear leukocyte-induced vasocontraction and endothelial dysfunction. 1179 66

The angiotensin-converting enzyme inhibitor (ACE-I) enalapril has been shown to lower elevated levels of circulating adhesion molecules (cAM) in critically ill patients. To delineate the mechanisms of this possibly beneficial effect of enalapril, we studied the acute effects of enalapril in a well-defined model of endotoxin-triggered, cytokine-mediated cAM up-regulation. In a randomized, controlled trial, 30 healthy male volunteers received 2 ng/kg lipopolysaccharide (LPS) after pretreatment with placebo or 20 mg/day enalapril for 5 days or with a single dose of 20 mg of enalapril 2 h before LPS infusion. LPS infusion increased TNF levels 300-fold above normal, circulating (c) E-selectin levels by 425% (CI, 359%-492%), and P-selectin, VCAM-1, ICAM-1, and von Willebrand factor levels by 47%-74%. LPS infusion also enhanced ICAM-1 and CD11b expression 2- to 3-fold on monocytes. However, no differences were seen between treatment groups (P > 0.05), despite 95% inhibition of ACE activity by enalapril. Inhibition of ACE activity by enalapril does not influence plasma indices of endothelial activation after endotoxin infusion in healthy individuals. Our results do not support the concept of a beneficial clinical effect of enalaprilat in septicemia.
 ...
PMID:Enalapril does not alter adhesion molecule levels in human endotoxemia. 1274 88

Basic and clinical observations suggest that thrombosis and inflammation are closely related. Here we addressed the role played by TNF-alpha in thrombus formation and growth in an in vivo mouse model. Using intravital microscopy, we show that systemic administration of TNF-alpha at doses found in sepsis transiently inhibits thrombus formation and delays arterial occlusion upon vascular injury. These results were reflected in a prolonged bleeding time. Platelets isolated from the TNF-alpha-treated mice showed a marked decrease in fibrinogen binding and P-selectin expression as well as reduced platelet aggregation in response to various agonists. In contrast, in vitro treatment of platelets with TNF-alpha did not affect their function. TNF receptor 1- and 2-deficient mice exhibited normal thrombogenesis in the presence of TNF-alpha. Additionally, the inhibitory effect of TNF-alpha was lost either after treatment with NG-monomethyl-l-arginine, an inhibitor of NO production, or in mice deficient for iNOS. These results indicate that under inflammatory conditions, when leukocytes need free passage to transmigrate into tissues, TNF-alpha decreases platelet activation and inhibits thrombi formation. This effect is not exerted directly on platelets but mediated through the rapid generation of NO in the vessel wall.
 ...
PMID:Antithrombotic activity of TNF-alpha. 1461 60


<< Previous 1 2 3 4 5 6 7 Next >>