Cytokine and fibrinogen response in patients undergoing open abdominal aortic aneurysm surgery.
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OBJECTIVES: To assess whether open abdominal aortic aneurysm (AAA) surgery influences cytokines and fibrinogen. METHODS: Twenty-three consecutive patients operated on for AAA were compared to 11 operated controls and 20 age-matched controls. Cubital blood was sampled pre-, intra- and postoperatively and femoral blood also sampled intraoperatively. RESULTS: Preoperatively, interleukin (Il)-6 was elevated in AAA patients. During aortic clamping, Il-6, Il-10 and monocyte chemoattractant protein-1 (MCP-1) increased significantly (p < 0.001, p < 0.01 and p < 0.05 respectively) while soluble interleukin-2 receptor (sIl-2R) and fibrinogen decreased significantly (p < 0.001 for both). After aortic declamping, Il-6, Il-10 and MCP-1 had further significant increases compared with levels during aortic clamping while sIl-2R had a further non-significant and fibrinogen a significant decrease (p < 0.05 in cubital and p < 0.001 in femoral blood). One week postoperatively Il-6, Il-10 and MCP-1 had all decreased but were still significantly elevated compared with baseline values while sIl-2R and fibrinogen showed an increase in comparison with baseline (p < 0.001 for both). Intraoperative levels of Il-6 and Il-10 showed a significant co-variation with the magnitude of operative trauma. CONCLUSIONS: These data indicate that open AAA surgery induces a profound inflammatory and coagulative response which persists at one week postoperatively. (+info)
Increase in interleukin-6 and fibrinogen in peripheral blood after swine dust inhalation.
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OBJECTIVES: The inhalation of dust from swine confinement buildings causes inflammatory responses in the airways with a rise of interleukin-6 (IL-6). The purpose of this study was to confirm the increase in serum IL-6 after inhalation of swine dust and investigate a possible increase in plasma fibrinogen. METHODS: Eight healthy nonsmoking volunteers inhaled dust for 4 hours inside a swine confinement building. Inhalable dust and endotoxin were sampled. The concentrations of IL-6 and fibrinogen were determined in serum and plasma. RESULTS: The study showed a clear increase in the concentrations of IL-6 and fibrinogen after exposure. CONCLUSIONS: As fibrinogen is an important risk factor for ischemic heart disease, the increased concentration of fibrinogen among persons exposed to swine dust may increase the risk for this disease. (+info)
Relationship between smoking and cardiovascular risk factors in the development of peripheral arterial disease and coronary artery disease: Edinburgh Artery Study.
(27/4604)
AIMS: The aim was to determine whether the effect of smoking on the development of peripheral or coronary artery disease might be mediated by other cardiovascular risk factors, including dietary antioxidant vitamin intake, serum low and high density lipoproteins, blood pressure, plasma fibrinogen, blood viscosity and markers of endothelial disturbance and fibrin turnover. METHODS AND RESULTS: 1592 men and women aged 55-74 years were selected at random from 11 general practices in Edinburgh, Scotland and followed-up for 5 years. The incidences of peripheral arterial disease and coronary artery disease were 5.1% and 11.1%, respectively. Both conditions were more common in moderate and heavy smokers than in never smokers: cigarette smoking was a stronger risk factor for peripheral arterial disease than for coronary artery disease. Smoking was associated with reduced dietary antioxidant vitamin intake, serum high density lipoprotein cholesterol and diastolic blood pressure and with increased alcohol intake, serum triglycerides, blood viscosity, plasma fibrinogen, and markers of endothelial disturbance (tissue plasminogen activator and von Willebrand factor antigens). Simultaneous adjustment for these risk factors reduced the relative risk of peripheral arterial disease only slightly, from 3.94 (95% CI 2.04, 7.62) to 2.72 (95% CI 1.13, 6.53) in heavy smokers and from 1.87 (95% CI 0.91, 3.85) to 1.70 (95% CI 0.72, 3.99) in moderate smokers. Similar adjustment also had little effect on the risk of coronary artery disease associated with smoking. CONCLUSION: The combined effect of smoking on the cardiovascular risk factors studied may explain part of its influence on peripheral and coronary arterial disease, but the majority of the effect appears to be due to other mechanisms. (+info)
Sequences within fibrinogen and intercellular adhesion molecule-1 (ICAM-1) modulate signals required for mitogenesis.
(28/4604)
The interaction of fibrinogen (Fg) with intercellular adhesion molecule-1 (ICAM) on B-lymphoid Raji cells results in mitogenesis (Gardiner, E. E., and D'Souza, S. E. (1997) J. Biol. Chem. 272, 15474-15480). Incubation of Raji with Fg resulted in the increased tyrosine phosphorylation of the receptor-associated tyrosine kinase, pp60(Src) and extracellular signal-regulated kinase-1 (ERK). The increase in ERK-1 phosphorylation was blocked by a peptide with sequence matching ICAM-1-(8-22) and corresponded to a decrease in ERK-1 enzymatic activity. 100 microM amounts of Fg peptide gamma-(117-133) caused an increase in tyrosine phosphorylation of ERK-1. These results are consistent with our previous report wherein ICAM-1-(8-22) blocked Fg-induced mitogenesis and Fg-gamma-(117-133) induced proliferation in Raji. The specific inhibitor of MEK, PD98059 (25 microM), abrogated the increased phosphorylation of ERK-1 and blocked Raji mitogenesis by >50%. Inhibitors of pp60(Src), geldanamycin (62 nM), and herbimycin A (2.5 microM) blocked >50% of Raji proliferation. These results indicate that the proliferation induced by Fg interactions with ICAM-1 is mediated in part by receptor-associated tyrosine kinases and ERK-1, and that the recognition sequences within Fg and ICAM-1 participate in the signaling process. (+info)
Thermal heterogeneity within human atherosclerotic coronary arteries detected in vivo: A new method of detection by application of a special thermography catheter.
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BACKGROUND: Activated macrophages play an important role in the pathogenesis of acute ischemic syndromes. It has been postulated that detection of heat released by activated inflammatory cells of atherosclerotic plaques may predict plaque rupture and thrombosis. Previous ex vivo studies have shown that there is thermal heterogeneity in human carotid atherosclerotic plaques. METHODS AND RESULTS: To measure the temperature of human arteries in vivo, we developed a catheter-based technique. Ninety patients (45 with normal coronary arteries, 15 with stable angina [SA], 15 with unstable angina [UA], and 15 with acute myocardial infarction [AMI]) were studied. The thermistor of the thermography catheter has a temperature accuracy of 0.05 degrees C, a time constant of 300 ms, and a spatial resolution of 0.5 mm. Temperature was constant within the arteries of the control subjects, whereas most atherosclerotic plaques showed higher temperature compared with healthy vessel wall. Temperature differences between atherosclerotic plaque and healthy vessel wall increased progressively from SA to AMI patients (difference of plaque temperature from background temperature, 0. 106+/-0.110 degrees C in SA, 0.683+/-0.347 degrees C in UA, and 1. 472+/-0.691 degrees C in AMI). Heterogeneity within the plaque was shown in 20%, 40%, and 67% of the patients with SA, UA, and AMI, respectively, whereas no heterogeneity was shown in the control subjects. CONCLUSIONS: Thermal heterogeneity within human atherosclerotic coronary arteries was shown in vivo by use of a special thermography catheter. This heterogeneity is larger in UA and AMI, suggesting that it may be related to the pathogenesis. (+info)
The phospholipase C inhibitor U73122 inhibits phorbol ester-induced platelet activation.
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Activation of phospholipase C (PLC) is a central component of the signal transduction process in numerous cells, including platelets. U73122 has been widely used as a selective PLC inhibitor. In the present study, the effects of U73122 on platelet function have been further examined. Platelets were stimulated with collagen (via PLC-gamma), the stable thromboxane mimetic U46619 (via PLC-beta), or phorbol myristate acetate (PMA) via protein kinase C (PKC). Consistent with inhibition of PLC, U73122 inhibited platelet aggregation and [3H]-serotonin release in response to collagen and U46619 in a concentration-dependent manner. Similarly, U73122 blocked collagen-induced release of thromboxane A2. U73122 also inhibited U46619-induced [32P]phosphatidic acid production and phosphorylation of the major PKC substrate, pleckstrin. U73122 had no effect on PMA-induced pleckstrin phosphorylation, [3H]-serotonin release, or intracellular vacuole formation. However, U73122 did inhibit PMA-induced platelet aggregation and fibrinogen binding. Overall, these results suggest that U73122, in addition to its inhibition of PLC, also affects PKC-independent events that interfere with platelet aggregation. (+info)
Molecular mechanisms of zinc-dependent leukocyte adhesion involving the urokinase receptor and beta2-integrins.
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The trace element Zinc (Zn2+) has been implicated as a mediator in host defense, yet the molecular basis for its extracellular functions remains obscure. Here, we demonstrate that Zn2+ can induce the adhesion of myelomonocytic cells to the endothelium, as well as to the provisional matrix proteins vitronectin (VN) and fibrinogen (FBG), which are pivotal steps for the recruitment of leukocytes into inflamed/injured tissue. Physiologic concentrations of Zn2+ increased the urokinase receptor (uPAR)-mediated adhesion of myelomonocytic cells to VN, whereas other divalent cations had smaller effects. Zn2+-induced cell adhesion to VN was abolished by cation chelators such as 1-10-phenanthroline, as well as by plasminogen activator inhibitor-1 (PAI-1) and a monoclonal antibody (MoAb) against uPAR. These characteristics could be recapitulated with a uPAR-transfected cell line emphasizing the specificity of this receptor system for Zn2+-dependent cell adhesion. Like urokinase (uPA), Zn2+ increased the binding of radiolabeled VN to uPAR-expressing cells, as well as the interaction of VN with immobilized uPAR in an isolated system. Moreover, Zn2+ enhanced leukocytic cell adhesion to FBG and endothelial cell monolayers by activating beta2-integrins. Instead of the direct beta2-integrin activation through the divalent cation binding site, Zn2+-induced integrin activation was mediated via uPAR, a crucial regulator of this system. The present study uncovers for the first time Zn2+-mediated cell adhesion mechanisms that may play a crucial role in modulating leukocyte adhesion to vessel wall components. (+info)
Fibrates suppress fibrinogen gene expression in rodents via activation of the peroxisome proliferator-activated receptor-alpha.
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Plasma fibrinogen levels have been identified as an important risk factor for cardiovascular diseases. Among the few compounds known to lower circulating fibrinogen levels in humans are certain fibrates. We have studied the regulation of fibrinogen gene expression by fibrates in rodents. Treatment of adult male rats with fenofibrate (0.5% [wt/wt] in the diet) for 7 days decreased hepatic Aalpha-, Bbeta-, and gamma-chain mRNA levels to 52% +/- 7%, 46% +/- 8%, and 81% +/- 19% of control values, respectively. In parallel, plasma fibrinogen concentrations were decreased to 63% +/- 7% of controls. The suppression of fibrinogen expression was dose-dependent and was already evident after 1 day at the highest dose of fenofibrate tested (0.5% [wt/wt]). Nuclear run-on experiments showed that the decrease in fibrinogen expression after fenofibrate occurred at the transcriptional level, as exemplified for the gene for the Aalpha-chain. Other fibrates tested showed similar effects on fibrinogen expression and transcription. The effect of fibrates is specific for peroxisome proliferator-activated receptor-alpha (PPARalpha) because a high-affinity ligand for PPARgamma, the thiazolidinedione BRL 49653, lowered triglyceride levels, but was unable to suppress fibrinogen expression. Direct evidence for the involvement of PPARalpha in the suppression of fibrinogen by fibrates was obtained using PPARalpha-null (-/-) mice. Compared with (+/+) mice, plasma fibrinogen levels in (-/-) mice were significantly higher (3.20 +/- 0.48 v 2.67 +/- 0.42 g/L). Also, hepatic fibrinogen Aalpha-chain mRNA levels were 25% +/- 11% higher in the (-/-) mice. On treatment with 0.2% (wt/wt) fenofibrate, a significant decrease in plasma fibrinogen to 77% +/- 10% of control levels and in hepatic fibrinogen Aalpha-chain mRNA levels to 65% +/- 12% of control levels was seen in (+/+) mice, but not in (-/-) mice. These studies show that PPARalpha regulates basal levels of plasma fibrinogen and establish that fibrate-suppressed expression of fibrinogen in rodents is mediated through PPARalpha. (+info)