Citations of BMS213/2TENCE
Persistent systemic inflammatory response after stent insertion in patients with malignant bile duct obstruction
Ballinger,A.B.; Woolley,J.A.; Ahmed,M.; Mulcahy,H.; Alstead,E.M.; Landon,J.; Clark,M.L.; Farthing,M.J.G.
Gut 1998;42:555-559.
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Abstract
Background[---]Surgery in patients with malignant bile duct obstruction is associated with high postoperative morbidity and mortality. Tumour necrosis factor [alpha] (TNF-[alpha]) plays a key role in the pathogenesis of these complications.Aims[---]To determine the effect of biliary drainage on plasma concentrations of TNF-[alpha], its soluble circulating receptors (sTNFr), and other proinflammatory cytokines.Methods[---]Plasma concentrations of TNF-[alpha], sTNFr-P75, interleukin 6 (IL-6), and IL-1[alpha] were measured in 25 patients with malignant bile duct obstruction before and after endoscopic stent insertion.Results[---]Mean serum bilirubin was 157 {micro}mol/l before stent insertion and 35.2 {micro}mol/l one week post stent insertion. There was complete relief of jaundice in 77% of patients by four weeks. Plasma concentrations of TNF-[alpha] and IL-1[alpha] were below the detection limit of the assays in all samples. Median plasma sTNFr-P75 in the cancer patients was 960 ng/l (range 400-6600) before stent insertion and remained unchanged at one and four weeks after stenting. Plasma sTNFr-P75 in cancer patients was significantly higher (p<0.01) than in healthy controls (250 (200-650) ng/l). Before stent insertion, plasma IL-6 concentrations were detectable (above 5 ng/l) in 17 (68%) patients. After relief of biliary obstruction IL-6 levels fell from a prestent median of 13.2 to less than 5 ng/l at one week after stent insertion. Plasma concentrations of IL-6 were undetectable in 76% of patients at this time.Conclusion[---]Activation of the TNF/sTNFr complex is unchanged after biliary drainage in patients with malignant bile duct obstruction. This may explain why preoperative drainage does not influence the high morbidity and mortality associated with surgery in these patients. (GUT 1998;42:555-559)Keywords: jaundice; tumour necrosis factor [alpha]; biliary drainage; pancreatic cancer
301
The type 1 lysophosphatidic acid receptor is a target for therapy in bone metastases
Boucharaba,Ahmed; Serre,Claire Marie; Guglielmi,Julien; Bordet,Jean Claude; Clezardin,Philippe; Peyruchaud,Olivier
Proceedings of the National Academy of Sciences U.S.A. 2006;103:9643-9648.
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Abstract
Platelet-derived lysophosphatidic acid (LPA) supports the progression of breast and ovarian cancer metastasis to bone. The mechanisms through which LPA promotes bone metastasis formation are, however, unknown. Here we report that silencing of the type 1 LPA receptor (LPA1) in cancer cells blocks the production of tumor-derived cytokines that are potent activators of osteoclast-mediated bone destruction and significantly reduces the progression of osteolytic bone metastases. Moreover, functional blockade of LPA action on its cognate receptor LPA1 using a pharmacological antagonist mimics the effects of silencing LPA1 in tumor cells in vitro and substantially reduces bone metastasis progression in animals. Overall, these results suggest that inhibition of platelet-derived LPA action on LPA1 expressed by tumor cells may be a promising therapeutic target for patients with bone metastases
694
Laparoscopy in patients over 60 years old: A prospective, randomized evaluation of laparoscopic versus open adnexectomy
Buchweitz,O.; Matthias,S.; Muller-Steinhardt,M.; Malik,E.
American Journal of Obstetrics and Gynecology 2005;193:1364-1368.
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Abstract
Objective To compare objective and subjective parameters of surgical stress following laparoscopic and open adnexectomy in patients older than 60 years old. Study design Twenty patients with a benign ovarian tumour were prospectively randomized to undergo adnexectomy by a laparoscopic or an open surgical procedure. Measurements included C-reactive protein; interleukin-6 before, during, and after surgery; intensity and duration of postoperative pain; and complications and recovery period. Statistical analysis consisted of analysis of variance and a Mann-Whitney U test. Results The levels of the interleukin-6 and C-reactive protein differed significantly between the 2 operative procedures (P = .013) in favor of the laparoscopic approach. The laparoscopic approach was associated with a reduction in operative morbidity, postoperative pain, analgesic requirement, and recovery period. Conclusions Minimally invasive surgery is of particular benefit to elderly patients if there is a plan in place for appropriate staging and treatment by laparotomy for malignancy. It should be the first choice and may help to reduce postoperative complications.
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Down-regulation of IL-8 expression in human airway epithelial cells through helper-dependent adenoviral-mediated RNA interference
Cao,Huibi; Wang,Anan; Martin,Bernard; Koehler,David; Zeitlin,Pamela; Tanawell,A.; Hu,Jim
Cell Res 2005;15:111-119.
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1187
Effect of Atorvastatin and Irbesartan, Alone and in Combination, on Postprandial Endothelial Dysfunction, Oxidative Stress, and Inflammation in Type 2 Diabetic Patients
Ceriello,Antonio; Assaloni,Roberta; Da Ros,Roberto; Maier,Amabile; Piconi,Ludovica; Quagliaro,Lisa; Esposito,Katherine; Giugliano,Dario
Circulation 2005;111:2518-2524.
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Abstract
Background-- Postprandial hypertriglyceridemia and hyperglycemia are considered risk factors for cardiovascular disease. Evidence suggests that postprandial hypertriglyceridemia and hyperglycemia induce endothelial dysfunction and inflammation through oxidative stress. Statins and angiotensin type 1 receptor blockers have been shown to reduce oxidative stress and inflammation, improving endothelial function. Methods and Results-- Twenty type 2 diabetic patients ate 3 different test meals: a high-fat meal, 75 g glucose alone, and a high-fat meal plus glucose. Glycemia, triglyceridemia, endothelial function, nitrotyrosine, C-reactive protein, intercellular adhesion molecule-1, and interleukin-6 were assayed during the tests. Subsequently, diabetics took atorvastatin 40 mg/d, irbesartan 300 mg/d, both, or placebo for 1 week. The 3 tests were performed again between 5 and 7 days after the start of each treatment. High-fat load and glucose alone produced a decrease in endothelial function and increases in nitrotyrosine, C-reactive protein, intercellular adhesion molecule-1, and interleukin-6. These effects were more pronounced when high-fat load and glucose were combined. Short-term atorvastatin and irbesartan treatments significantly counterbalanced these phenomena, and their combination was more effective than either therapy alone. Conclusions-- This study confirms an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial function and inflammation, suggesting oxidative stress as a common mediator of such an effect. Short-term treatment with atorvastatin and irbesartan may counterbalance this phenomenon; the combination of the 2 compounds is most effective
403
Leukemia-Derived Immature Dendritic Cells Differentiate into Functionally Competent Mature Dendritic Cells That Efficiently Stimulate T Cell Responses
Cignetti,Alessandro; Vallario,Antonella; Roato,Ilaria; Circosta,Paola; Allione,Bernardino; Casorzo,Laura; Ghia,Paolo; Caligaris-Cappio,Federico
The Journal of Immunology 2004;173:2855-2865.
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Abstract
Primary acute myeloid leukemia cells can be induced to differentiate into dendritic cells (DC). In the presence of GM-CSF, TNF-{alpha}, and/or IL-4, leukemia-derived DC are obtained that display features of immature DC (i-DC). The aim of this study was to determine whether i-DC of leukemic origin could be further differentiated into mature DC (m-DC) and to evaluate the possibility that leukemic m-DC could be effective in vivo as a tumor vaccine. Using CD40L as maturating agent, we show that leukemic i-DC can differentiate into cells that fulfill the phenotypic criteria of m-DC and, compared with normal counterparts, are functionally competent in vitro in terms of: 1) production of cytokines that support T cell activation and proliferation and drive Th1 polarization; 2) generation of autologous CD8+ CTLs and CD4+ T cells that are MHC-restricted and leukemia-specific; 3) migration from tissues to lymph nodes; 4) amplification of Ag presentation by monocyte attraction; 5) attraction of naive/resting and activated T cells. Irradiation of leukemic i-DC after CD40L stimulation did not affect their differentiating and functional capacity. Our data indicate that acute myeloid leukemia cells can fully differentiate into functionally competent m-DC and lay the ground for testing their efficacy as a tumor vaccine
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M protein mediated adhesion of M type 24 Streptococcus pyogenes stimulates release of interleukin-6 by HEp-2 tissue culture cells
Courtney,Harry S.; Ofek,Itzhak; Hasty,David L.
FEMS Microbiology Letters 1997;151:65-70.
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Abstract
Abstract We investigated the contributions of lipoteichoic acid and M protein to reversible and irreversible adhesion of group A streptococci and the effects of such adhesion on release of interleukin-6. Streptococci in which lipoteichoic acid was masked by the hyaluronate capsule were readily washed from HEp-2 cells, indicating no attachment. Unencapsulated, M-negative streptococci in which lipoteichoic acid was exposed were removed more slowly, indicating loose attachment. Only unencapsulated streptococci that expressed both lipoteichoic acid and M protein remained stably adherent to HEp-2 cells throughout multiple washes. Streptococci expressing both M protein and lipoteichoic acid induced release of interleukin-6 from HEp-2 cells, whereas an isogenic, M-negative mutant failed to induce release of interleukin-6. These data suggest that lipoteichoic acid mediates reversible adhesion and that M protein is required for irreversible adhesion and for inducing release of interleukin-6 from HEp-2 cells
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Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes
Creely,Steven James; McTernan,Philip Gerard; Kusminski,Christine Maria; Fisher,ffolliot Martin; Khanolkar,Manish; Evans,Mark; Harte,Alison louise; Kumar,Sudhesh
Endocrinology and Metabolism 2006;292:00302› Link
Abstract
Type-2 diabetes (T2DM) is associated with chronic low-grade inflammation. Adipose tissue (AT) may represent an important site of inflammation. 3T3-L1 studies have demonstrated that lipopolysaccharide (LPS) activates toll like receptors (TLRs) to cause inflammation. For this study we (1) examined activation of TLRs and adipocytokines by LPS in human abdominal subcutaneous (AbdSc) adipocytes; (2) examined blockade of nuclear factor-kappa B (NF{kappa}B) in human AbdSc adipocytes (3) examined the innate immune pathway in AbdSc AT from lean, obese and T2DM subjects; and (4) examined the association of circulating LPS in T2DM subjects. LPS increased TLR-2 protein expression two-fold (p<0.05). Treatment of AbdSc adipocytes with LPS caused a significant increase in TNF-{alpha} and IL-6 secretion (IL-6, Control: 2.7{+/-}0.5ng/mL vs. LPS: 4.8{+/-}0.3ng/mL; p<0.001; TNF-{alpha}, Control: 1.0{+/-}0.83pg/mL vs. LPS: 32.8{+/-}6.23pg/mL; p<0.001). NF{kappa}B inhibitor reduced IL-6 in AbdSc adipocytes (Control: 2.7{+/-}0.5ng/mL vs. NF{kappa}B inhibitor: 2.1{+/-}0.4 ng/mL; p<0.001). AbdSc AT protein expression for TLRs, MyD88, TRAF6, NF{kappa}B was increased in T2DM's (p<0.05). Circulating LPS was 76% higher in T2DM subjects compared with matched controls. LPS correlated with insulin in controls (r=0.678, p<0.0001). Rosiglitazone significantly reduced both fasting serum insulin levels (reduced by 51%, p=0.0395) and serum LPS (reduced by 35%, p=0.0139) in a sub-group of previously untreated T2DM patients. In summary, our results suggest that T2DM is associated with increased endotoxemia, with adipose tissue able to initiate an innate immune response. Thus, increased adiposity may increase pro-inflammatory cytokines and therefore contribute to the pathogenic risk of T2DM
702
Inflammatory responses associated with acute coronary syndrome up-regulate IRAK-M and induce endotoxin tolerance in circulating monocytes
del Fresno,Carlos; Soler-Rangel,Llanos; Soares-Schanoski,Alessandra; Gomez-Pina,Vanesa; Gonzalez-Leon,Maria Carmen; Gomez-Garcia,Lourdes; Mendoza-Barbera,Elena; Rodriguez-Rojas,Alexandro; Garcia,Felipe; Fuentes-Prior,Pablo; Arnalich,Francisco; Lopez-Collazo,Eduardo
Journal of Endotoxin Research 2007;13:39-52.
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Abstract
Acute coronary syndrome (ACS) groups different cardiac diseases whose development is associated with inflammation. Here we have analyzed the levels of inflammatory cytokines and of members of the TLR/IRAK pathway including IRAK-M in monocytes from ACS patients classified as either UA (unstable angina), STEMI (ST-elevation myocardial infarction) or NSTEMI (non-ST-elevation myocardial infarction). Circulating monocytes from all patients, but not from healthy individuals, showed high levels of pro-inflammatory cytokines, TNF-{alpha} and IL-6, as well as of IRAK-M and IL-10. TLR4 was also up-regulated, but IRAK-1, IRAK-4 and MyD88 levels were similar in patients and controls. Further, we investigated the consequences of cytokines/IRAK-M expression on the innate immune response to endotoxin. Ex vivo responses to LPS were markedly attenuated in patient monocytes compared to controls. Control monocytes cultured for 6 h in supplemented medium (10% serum from ACS patients) expressed IRAK-M, and LPS stimulation failed to induce TNF-{alpha} and IL-6 in these cultures. Pre-incubation of the serum with a blocking anti-TNF-{alpha} antibody reduced this endotoxin tolerance effect, suggesting that TNF-{alpha} controls this phenomenon, at least partially. We show for the first time that inflammatory responses associated with ACS induce an unresponsiveness state to endotoxin challenge in circulating monocytes, which correlates with expression of IRAK-M, TLR4 and IL-10. The magnitude of this response varies according to the clinical condition (UA, STEMI or NSTEMI), and is regulated by TNF-{alpha}
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Mechanism of Complement Activation and Its Role in the Inflammatory Response After Thoracoabdominal Aortic Aneurysm Repair
Fiane,Arnt E.; Videm,Vibeke; Lingaas,Per S.; Heggelund,Lars; Nielsen,Erik W.; Geiran,Odd R.; Fung,Michael; Mollnes,Tom E.
Circulation 2003;108:849-856.
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Abstract
Background-- Complement activation contributes to ischemia-reperfusion injury. Patients undergoing thoracoabdominal aortic aneurysm (TAAA) repair suffer extensive ischemia-reperfusion and considerable systemic inflammation. Methods and Results-- The degree and mechanism of complement activation and its role in inflammation were investigated in 19 patients undergoing TAAA repair. Patients undergoing open infrarenal aortic surgery (n=5) or endovascular descending aortic aneurysm repair (n=6) served as control subjects. Substantial complement activation was seen in TAAA patients but not in controls. C1rs-C1-inhibitor complexes increased moderately, whereas C4bc, C3bBbP, C3bc, and the terminal SC5b-9 complex (TCC) increased markedly after reperfusion, reaching a maximum 8 hours after reperfusion. Interleukin (IL)-1{beta}, tumor necrosis factor {alpha} (TNF-{alpha}), and IL-8 increased significantly in TAAA patients but not in controls, peaking at 24 hours postoperatively and correlating closely with the degree of complement activation. IL-6 and IL-10 increased to a maximum 8 hours after reperfusion in the TAAA patients, were not correlated with complement activation, and increased moderately in the control subjects. Myeloperoxidase and lactoferrin increased markedly before reperfusion in all groups, whereas sICAM-1, sP-selectin, and sE-selectin were unchanged. No increase was observed in complement activation products, IL-1{beta}, TNF-{alpha}, or IL-8 in a mannose-binding lectin (MBL)-deficient TAAA patient, whereas IL-6, IL-10, myeloperoxidase, and lactoferrin increased as in the controls. Two other MBL-deficient TAAA patients receiving plasma attained significant MBL levels and showed complement and cytokine patterns identical to the MBL-sufficient TAAA patients. Conclusions-- The data suggest that complement activation during TAAA repair is MBL mediated, amplified through the alternative pathway, and responsible in part for the inflammatory response
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Anti-inflammatory effect of virgin olive oil in stable coronary disease patients: a randomized, crossover, controlled trial
Fito,M.; Cladellas,M.; de la Torre,R.; Marti,J.; Munoz,D.; Schroder,H.; Alcantara,M.; Pujadas-Bastardes,M.; Marrugat,J.; Lopez-Sabater,M.; Bruguera,J.; Covas,M.
Eur J Clin Nutr 2007;doi: 10.10:› Link
Abstract
Objectives: To assess the effect of two similar olive oils, but with differences in their phenolic compounds (powerful antioxidant compounds), on inflammatory markers in stable coronary heart disease patients.Design: Placebo-controlled, crossover, randomized trial.Setting: Cardiology Department of Hospital del Mar and Institut Municipal d'Investigació Mèdica (Barcelona).Subjects: Twenty-eight stable coronary heart disease patients.Interventions: A raw daily dose of 50 ml of virgin and refined olive oil (ROO) was sequentially administered over two periods of 3-weeks, preceded by 2-week washout periods in which ROO was used.Results: Interleukin-6 (P<0.002) and C-reactive protein (P=0.024) decreased after virgin olive oil intervention. No changes were observed in soluble intercellular and vascular adhesion molecules, glucose and lipid profile.Conclusions: Consumption of virgin olive oil, could provide beneficial effects in stable coronary heart disease patients as an additional intervention to the pharmacological treatment.
1191
Nitric oxide may contribute to nocturnal hemodynamic changes in cirrhotic patients
Genesca,Joan; Segura,Rosa; Gonzalez,Antonio; Catalan,Robert; Marti,Ramon; Torregrosa,Mireia; Cereto,Ferran; Martinez,Moises; Esteban,Rafael; Guardia,Jaime
The American Journal of Gastroenterology 2000;95:1539-1544.
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Abstract
OBJECTIVE: Patients with liver cirrhosis have a nocturnal worsening of hemodynamic parameters that has been associated with an increased risk of variceal bleeding at nighttime. The aim of this study was to investigate whether nitric oxide and cytokines are implicated in these hemodynamic changes. METHODS: Ten cirrhotic patients and eight controls were studied. Mean blood pressure, heart rate, plasma norepinephrine, tumor necrosis factor alpha and interleukin-6 levels, and serum nitrite + nitrate levels were determined at 0800, 1600, and 2400 h. All determinations were performed in supine rest and at least 4 h after meals. In a second study, nitrite + nitrate levels were assessed in 10 cirrhotic patients before and after eating a standard meal. RESULTS: Mean arterial pressure levels that were always lower in the patient group showed a nocturnal decrease in both groups of subjects. Heart rate values that were always higher in cirrhotic patients showed a nocturnal fall in controls, whereas cirrhotics maintained elevated values at nighttime. Norepinephrine levels were higher in cirrhotics and maintained similar values during the study, whereas controls had a significant nocturnal decrease. Nitrite + nitrate levels that were higher in cirrhotic patients showed a significant mean increase of 40% from morning (0800 h) to night (2400 h) in the patient group, whereas in controls no change was observed ( p< 0.05 ). Tumor necrosis factor alpha and interleukin-6 levels did not change either in patients or controls during the entire period. Cirrhotic patients with or without ascites maintained a pattern of hemodynamic and biochemical changes similar to the pattern observed in the entire group of patients. Finally, no changes in serum nitrite + nitrate levels were observed in patients before and after eating the standard meal. CONCLUSION: An increased nocturnal nitric oxide production might contribute to the hemodynamic changes observed in cirrhotic patients during nighttime
657
Melatonin reduces oxidative stress in surgical neonates
Gitto,E.; Romeo,C.; Reiter,R.J.; Impellizzeri,P.; Pesce,S.; Basile,M.; Antonuccio,P.; Trimarchi,G.; Gentile,C.; Barberi,I.
Journal of Pediatric Surgery 2004;39:184-189.
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Abstract
Background/purpose Cytokines are inflammatory mediators found in the circulation after surgery. Newborns have less protection against oxidation and are very susceptible to free radical oxidative damage. Melatonin has been reported recently to reduce oxidative stress in neonates with sepsis, asphyxia, and respiratory distress. The aim of this study has been to determine if melatonin would lower interleukin (IL)-6, IL-8, tumor necrosis factor alpha (TNF-a) and nitrite/nitrate (NOx) levels and modify serum inflammation parameters, improving the clinical course of surgical neonates. Methods Ten newborns (group 1), 5 with surgical malformations and respiratory distress (group 1a) and 5 with isolated abdominal surgical malformations (group 1b) received a total of 10 doses of melatonin (10 mg/kg) at defined times interval for 72 hours. The treatment was started within 3 hours after the end of surgery. Ten surgical neonates (group 2), did not receive melatonin. Twenty healthy neonates (group 3) served as control. Blood samples were collected at the end of operation; before treatment with the antioxidant; and 24 hours 72 hours, and 7 days after start of treatment with melatonin or placebo, respectively. Results Postoperative value of cytokines and NOx levels of groups 1 and 2 were significantly higher than group 3. Compared with group 1b, group 2 displayed significantly higher cytokines and NOx levels at 24 hours, 72 hours, and at 7 days. In group 1a the immediate postoperative values of cytokines were significantly higher than group 1b and group 2, but a significant improvement was observed after administration of melatonin with significantly lower levels of IL-6 and IL-8 with respect to group 2. An improvement of clinical outcome was observed by progressive reduction of clinical parameters of inflammation. Conclusions Melatonin reduces cytokines and NOx levels showing potent antioxidant properties with improvement in clinical outcome. Further studies are warranted to define, on larger numbers, the role of melatonin in surgical patients.
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Correlation among cytokines, bronchopulmonary dysplasia and modality of ventilation in preterm newborns: improvement with melatonin treatment
Gitto,Eloisa; Reiter,Russel J.; Sabatino,Giuseppe; Buonocore,Giuseppe; Romeo,Carmelo; Gitto,Placido; Bugge,Concetta; Trimarchi,Giuseppe; Barberi,Ignazio
Journal of Pineal Research 2005;39:287-293.
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Abstract
Abstract: Improved survival because of advances in neonatal care has resulted in an increased number of infants at risk for chronic lung disease. Even though the etiology of lung injury is multifactorial, recent animal and clinical data indicate that pulmonary damage depends in large part on the ventilatory strategies used. Ventilator-associated lung injury was believed to result from the use of high pressure, thus, the term barotraumas. This trauma is believed to involve free-radical damage. Oxidant injury is a serious cause of lung injury. In the present study, 110 newborns with respiratory distress syndrome were studied; 55 were treated with melatonin and the other 55 with placebo. All the subjects were mechanically ventilated with or without guaranteed volume. Proinflammatory cytokines [interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-alpha] were measured in tracheobronchial aspirate and the clinical outcome was evaluated. Melatonin treatment reduced the proinflammatory cytokines and improved the clinical outcome. The beneficial action of melatonin presumably related to its antioxidative actions
577
Clinical performance and biocompatibility of poly(2-methoxyethylacrylate)--coated extracorporeal circuits
Gunaydin,Serdar; Farsak,Bora; Kocakulak,Mustafa; Sari,Tamer; Yorgancioglu,Cem; Zorlutuna,Yaman
Annals of Thoracic Surgery 2002;74:819-824.
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Abstract
Background. Poly(2-methoxyethylacrylate) is an amphiphilic organic polymer consisting of a hydrophobic backbone with pendant hydrophilic groups that has been reported to reduce protein and platelet adsorption in in vitro and ex vivo studies. Methods. Sixty patients undergoing three-vessel coronary artery bypass grafting were divided into two equal groups. Group 1 had operation with Capiox poly(2-methoxyethylacrylate) coated SX18R oxygenators with noncoated circuits, and group 2 had operation with all noncoated circuits. Hemodynamic variables, blood and urine test results, hematologic variables, complement fractions, C3a and C4d, and interleukin-6 levels were documented preoperatively (T1), on cardiopulmonary bypass (T2), before cessation of cardiopulmonary bypass (T3), after protamine sulfate reversal (T4), and on the first postoperative day (T5). Protein electrophoresis was performed at T1 and T5. Blood cell adhesion and aggregation on fibers were analyzed with optical microscopy, and desorbed protein was evaluated quantitatively by a spectrophotometer using samples obtained when the oxygenators were dismantled after cardiopulmonary bypass. Results. Platelet counts in group 1 demonstrated significant differences at T3, T4, and T5 (p < 0.05) versus group 2 and white blood cell counts in group 1 versus group 2, at counts T4 and T5. Albumin levels were significantly better preserved in group 1 at T4, and T5 and fibrinogen levels, at T3 and T5 (p < 0.05). On electrophoresis, the postoperative albumin level was 57.9% {+/-} 3% in group 1 versus 50.2% {+/-} 3% in group 2 (p < 0.05). Postoperative hemorrhage was 452 {+/-} 35 mL in group 1 and 612 {+/-} 35 mL in group 2 (p < 0.05). Duration of intubation was significantly lower (p < 0.05) in group 1, as was need of blood transfusion (p < 0.01). More platelet adhesion and aggregation were demonstrated on noncoated oxygenator fibers. The amount of desorbed protein was 0.13 {+/-} 0.01 mg/dL versus 0.012 {+/-} 0.001 mg/dL (p < 0.001) on noncoated versus coated fibers, respectively. Conclusions. Poly(2-methoxyethylacrylate)--coated oxygenators reduce platelet adhesion, platelet aggregation and protein adsorption. This surface provides a better perioperative clinical status through platelet-, albumin-, and fibrinogen-sparing effects
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Tumor Necrosis Factor-{alpha}-Related Intraperitoneal Release of CA 125 in Cirrhotic Patients with Sterile Ascites
Kalambokis,Georgios; Kostoula,Ageliki; Economou,Michalis; Tsianos,Epameinondas V.
Clinical Chemistry 2005;51:2207-2208.
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Abstract
Cancer antigen 125 (CA 125) is commonly increased in liver cirrhosis and increased even more in ascitic fluid. Peritoneal mesothelial cells can synthesize CA 125, and proliferative mesothelial cells stain for it. It is not clear whether mechanical stress related to ascites can stimulate mesothelium to produce CA 125 or whether clearance of CA 125 by the diseased liver is impaired. Mesothelial cells may regulate intraperitoneal antibacterial defense mechanisms. Cultured mesothelial cells produce cytokines, including interleukin-6 (IL-6) and IL-8, on stimulation with tumor necrosis factor-á (TNF-á) or IL-1ß. Human peritoneal macrophages produce TNF-á and IL-1ß after incubation with bacteria, which in turn can trigger mesothelial cells to produce IL-8 and IL-6. High serum concentrations of TNF-á and IL-6, possibly of intraabdominal origin, have been observed in cirrhotic patients with sterile ascites. We investigated whether the intraperitoneal release of CA 125 in cirrhotic patients with sterile ascites could be influenced by the stimulation of mesothelial cells with proinflammatory cytokines, such as TNF-á.
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Keratinocyte-derived cytokines after photodynamic therapy and their paracrine induction of matrix metalloproteinases in fibroblasts
Karrer,S.; Bosserhoff,A.K.; Weiderer,P.; Landthaler,M.; Szeimies,R.M.
British Journal of Dermatology 2004;151:776-783.
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Abstract
Summary Background Recent studies have shown that collagen-degrading matrix metalloproteinase (MMP)-1 and MMP-3 are produced by fibroblasts in response to photodynamic therapy (PDT) with 5-aminolaevulinic acid (ALA) and are considered to be involved in the antisclerotic effects of ALA-PDT observed in the treatment of localized scleroderma. Objectives As the primary target of topical PDT is epidermal keratinocytes, we studied the indirect participation of keratinocytes in the production of MMPs and collagen by dermal fibroblasts. Methods Keratinocytes were treated with sublethal doses of ALA (100 umol L-1) and red light. The conditioned media were collected 24 h after PDT and primary human fibroblasts were exposed to these media for 6-48 h. Further, a coculture model, keratinocytes seeded on to collagen type IV-coated transwells in the upper chamber and fibroblasts in the lower chamber, was used to study paracrine effects of keratinocytes after PDT. Results Keratinocyte supernatants after PDT showed a significant, up to 10-fold increase of interleukin (IL)-1alpha and a 2.5-fold increase of tumour necrosis factor-alpha as determined by enzyme-linked immunosorbent assay, while IL-6, MMP-1 and MMP-3 were not altered significantly. Fibroblasts treated with keratinocyte-conditioned media after PDT showed an induction of MMP-1 and MMP-3 protein levels up to threefold in both models used, suggesting that ALA-PDT modulates MMP-1 and MMP-3 production via indirect mechanisms. Collagen type I mRNA expression by fibroblasts was not altered significantly in either model. The addition of an IL-1 receptor antagonist to the keratinocyte-conditioned media completely inhibited the induction of MMP-1 and MMP-3 in stimulated fibroblasts, suggesting that IL-1 is mainly responsible for the observed paracrine effects. Conclusions We present evidence that PDT can trigger MMP production in dermal fibroblasts not only directly as has been already shown, but also by an indirect paracrine loop mediated by soluble factors released by epidermal keratinocytes
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Role of amiodarone on the systemic inflammatory response induced by cardiac surgery: proinflammatory actions: [Role de l'amiodarone sur la reaction inflammatoire systemique provoquee par la chirurgie cardiaque : actions pro-inflammatoires]
Karth,Georg Delle; Buberl,Anton; Nikfardjam,Mariam; Meyer,Brigitte; Wollenek,Gregor; Grimm,Michael; Lassnigg,Andrea; Brannath,Werner; Hiesmayr,Michael; Heinz,Gottfried
Canadian Journal of Anesthesia 2007;54:262-268.
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Abstract
Purpose: Amiodarone (AMIO), a widely used anti-arrhythmic drug, has been shown to reduce the incidence of atrial fibrillation after cardiac surgery and also to exert immunomodulatory actions in vitro and proinflammatory effects in vivo. The present study investigated the immunomodulatory properties of AMIO in the inflammatory response induced by cardiac surgery with cardiopulmonary bypass (CPB). Methods: In this double-blind, placebo-controlled trial, 20 patients undergoing elective coronary artery bypass graft were randomized to receive placebo or AMIO 600 mg{middle dot}day-1 orally for seven days before surgery and 45 mg{middle dot}hr-1 intravenously for 48 hr postoperatively. Plasma levels of the proinflammatory markers C-reactive protein (CRP), fibrinogen (FBG), tumour necrosis factor (TNF)-{alpha}, interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1, and the antiinflammatory marker IL-10, were compared before and after surgery. Results: Ninety-six hours after start of surgery, plasma levels of FBG had more than doubled (2.2 {+/-} 0.5-fold increase, P < 0.0001). Overall, FBG formation was significantly increased in the AMIO group (P = 0.048). Monocyte chemoattractant protein 1 secretion transiently increased four hours after start of surgery (6.6 {+/-} 4.5-fold increase) but rapidly declined thereafter, (P < 0.0001). There was a trend toward higher MCP-1 plasma concentrations in the AMIO group (P = 0.13). The plasma levels of CRP, TNF-{alpha}, IL-6 and Il-10 changed significantly over time, but were not altered by AMIO treatment. Conclusion: In the inflammatory response induced by cardiac surgery with CPB, our data suggest that AMIO treatment is associated with a selective trend toward proinflammatory actions
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The effect of (1->3)-
Kubala,L.; Ruzickova,J.; Nickova,K.; Sandula,J.; Ciz,M.; Lojek,A.
Carbohydrate Research 2003;338:2835-2840.
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Abstract
(1->3)-ß-d-glucans are known as potent inductors of humoral and cell-mediated immunity in humans and animals. (1->3)-ß-d-glucans isolated from various sources differ in their chemical structure and physical parameters and consequently in their immunomodulatory potential. In this study the immunomodulatory activity of two (1->3)-ß-d-glucans schizophyllan (SPG) and carboxymethylglucan (CMG) was determined and compared on human blood leukocytes in vitro. Both SPG and CMG activated blood phagocytes and lymphocytes as demonstrated by increased whole blood production of reactive oxygen species, by increased production of pro-inflammatory cytokines IL-6, IL-8, and TNF-á, by increased surface expression of CD69 on lymphocytes, and by altered expression of CD11b and CD62L on polymorphonuclear leukocytes and monocytes. SPG demonstrated a significantly higher potential to stimulate blood phagocytes and production of selected pro-inflammatory cytokines than CMG. The higher potency of SPG to stimulate human blood phagocytes in vitro could be caused by factors such as higher branching frequencies or neutral polymer charge of SPG or different conformation in solution if compared with CMG.
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Hyperleptinaemia and chronic inflammation after peritonitis predicts poor nutritional status and mortality in patients on peritoneal dialysis
Lam,Man Fai; Leung,Joseph C.K.; Lo,Wai Kei; Tam,Sidney; Chong,Mei ching; Lui,Sing Leung; Tse,Kai Chung; Chan,Tak Mao; Lai,Kar Neng
Nephrology Dialysis Transplantation 2007;22:1445-1450.
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Abstract
Background. The serum leptin level is elevated in patients undergoing peritoneal dialysis (PD) and associated with a loss of lean body mass. The nutritional status of PD patients may further be worsened following peritonitis. We investigated the association between hyperleptinaemia, inflammation and malnourishment in PD-related peritonitis. Methods. We conducted a prospective study on PD patients who developed peritonitis. Blood samples were obtained as baseline (D0) before the onset of peritonitis, and once peritonitis developed, leptin, adiponectin (ADPN) and other inflammatory markers were collected, on day 1 (D1), day 7 (D7) and day 42 (D42) of peritonitis. Patients were followed-up for any censor event or 1 year after peritonitis. Results. Forty-two patients with a mean age of 62.9 {+/-} 13.2 years were recruited. Fourteen (33.3%) were diabetic. The serum leptin levels increased significantly from baseline to day 1 and 7, but fell back to the premorbid state at day 42. In contrast, the ADPN level decreased from a baseline value of 15.60 {+/-} 10.4 {micro}g/ml to 13.01 {+/-} 8.1 {micro}g/ml on day 1 (P = 0.01) but rose to 14.39 {+/-} 8.9 {micro}g/ml on day 7 (P = 0.28) and 13.87 {+/-} 7.9 {micro}g/ml on day 42 (P = 0.21). High-sensitivity C-reactive protein (hs-CRP) increased significantly from baseline to day 1, 7 and even at day 42. The lean body mass (LBM) and nutritional markers decreased significantly after peritonitis. For patients with high hs-CRP (>3.0 mg/l) at day 42, there was a higher mortality rate than for those with lower hs-CRP (<3.0 mg/l, P = 0.02), even if they were in clinical remission of peritonitis. Conclusions. Our study confirmed an increase in serum leptin during acute peritonitis and a prolonged course of systemic inflammation after apparent clinical remission of peritonitis. These factors related to the persistent chronic inflammation may contribute to the development of malnourishment and poor survival rate
826
Proinflammatory cytokine (IL-1beta, IL-6, IL-12, IL-18 and TNF-alpha) levels in sera of patients with subacute cutaneous lupus erythematosus (SCLE)
Maczynska,Iwona; Millo,Barbara; Ratajczak-StefaDska,Violetta; Maleszka,Romuald; Szych,Zbigniew; Kurpisz,Maciej; Giedrys-Kalemba,Stefania
Immunology letters 2006;102:79-82.
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Abstract
Subacute cutaneous lupus erythematosus (SCLE) is a subset of lupus erythematosus that identifies patients with clinically recognized erythematous, nonscarring lesions, photosensitivity and serologic abnormalities. Anti-Ro (SS-A) antibodies are considered to be a typical immunopathologic marker of SCLE. Autoimmune diseases have been also characterized by the disturbances in the cytokine network. The aim of this study was to compare the concentrations of proinflammatory cytokines (IL-1beta, IL-6, IL-12, IL-18 and TNF-alpha) in serum of ANA-positive (antibody against nuclear antigen) and ANA-negative patients with SCLE. Sera samples were collected from 15 patients with SCLE (9 ANA-positive and 6 ANA-negative ones). The preliminary identification of autoantibodies as well as their titers was determined on HEp-2 cells using IIF method. Western blotting (EUROIMMUN) was applied to verify the results of IIF. Proinflammatory cytokine concentrations in the patients' sera samples were determined by enzyme-linked immunosorbent assay (ELISA) (Bender MedSystems). The levels of IL-12 were higher in ANA-positive patients than in ANA-negative subgroups [median (interquartile range), 330 pg/ml (128-708 pg/ml) versus 39.4 pg/ml (31.25-80 pg/ml)]. Similar differences were observed in the level of IL-18 [median (interquartile range), 508.4 pg/ml (180-1222 pg/ml) versus 100.5 pg/ml (78.1-154 pg/ml)]. The differences in TNF-alpha levels between the groups of ANA-positive and ANA-negative patients were at the verge of statistical significance, p<0.05. The sera levels of IL-1beta and IL-6 were low and of no significant difference concerning the ANA-positive and ANA-negative subgroups. Since serum levels of IL-12 and IL-18 were higher in ANA-positive patients than in ANA-negative patients, these cytokines might play an important role in the inflammatory process in SCLE.
1007
Raloxifene therapy interacts with serum osteoprotegerin in postmenopausal women
Messalli,E.M.; Mainini,G.; Scaffa,C.; Cafiero,A.; Salzillo,P.L.; Ragucci,A.; Cobellis,L.
Maturitas 2007;56:38-44.
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Abstract
Osteoprotegerin (OPG) is a protein expressed by osteoblasts that, linking the receptor activator of nuclear factor ?B (RANK) ligand (RANKL), produced by osteoblasts, blocks the process of osteoclastic differentiation and modulates osteoclastic apoptosis. Raloxifene (RAL) stimulates the production of OPG from osteoblasts, as demonstrated in vitro, carring out their antiresorption activity, at least in part, as means of the OPG/RANK/RANKL system. The aim of this study was to evaluate in vivo if the RAL treatment of postmenopausal women was associated to changes in serum OPG; moreover, to evaluate the serum changes of bone turnover modulators interleukin-6 (IL-6) and C-telopeptides of type-1 collagen (CrossLaps). Methods A prospective, randomized, placebo-controlled study was designed. A group of consecutive healthy postmenopausal women (n = 40) referred to II Menopause Centre of the Department of Gynaecology of Second University of Naples for climacteric syndrome was enrolled and divided in two groups: (n = 20) postmenopausal women received for 6 months oral raloxifene (60 mg/day) versus (n = 20) postmenopausal women received placebo tablets. Results Serum OPG levels in postmenopausal women after RAL treatment are statistically significant increased (P < 0.001) versus baseline (P = 0.007) versus placebo. Conclusions These in vivo data demonstrate that RAL could improve osteoporosis, also through an increase of OPG production by osteoblasts.
1020
Chemotherapy induces inflammatory response in breast cancer patients
Michlmayr A.,S.Baumann,M.Zellner,C.Burghuber,P.Schuch,C.Wenzel,R.Bartsch,U.Pluschnig,I.Rech-Weichselbraun,G.Steger,R.Jakesz,M.Gnant and T.Bachleitner-Hofmann,M.Bergmann,R.Oehler
Keystonesymposia, Inflammation, Microenvironment and Cancer 2008;Abstract
Chemotherapeutic treatment of breast cancer patients supposedly mediates its effect via direct elimination of tumor cells. However, there is growing evidence that activation of immune cells in the tumor micro environment is essential for tumor regression. We investigated whether chemotherapy is associated with an inflammatory response which is detectable also in the peripheral blood. Blood was taken from 24 breast cancer patients before and 4 days after receiving the first course of neoadjuvant chemotherapy (epirubicin/docetaxel). This combination therapy leads to substantial tumor regression in about 50% of patients. To assess the inflammatory response we performed an analysis of 17 different inflammatory mediators using a beads based multiplex immunoassay. Systemic IL-6 and IL-10 levels increased in response to chemotherapy while sPECAM and sICAM-3 levels decreased. These results were verified by ELISA (p<0.01). To get a broader view of the effect of chemotherapy a proteomic analysis was performed using 2D-DIGE. Thirty-one out of 642 protein spots showed a more than 1.4 fold (p < 0.05) change within 4 days of chemotherapy including complement factors C1, C3 and C4, alpha2HSglycoprotein, and alpha1-anti chymotrypsin. These proteins are induced in the course of acute phase response during inflammation. These data show that chemotherapy induces inflammation in breast cancer patients. However, it cannot be concluded whether this occurs due to a direct effect of treatment on cancer cells or to a side effect on other tissues. The degree of protein induction varied between patients. Future studies are planned to clarify whether such variations are associated with the clinical response rate to therapy.
1288
Regulation by complement C3a and C5a anaphylatoxins of cytokine production in human umbilical vein endothelial cells
MONSINJON,T.I.P.H.; GASQUE,P.H.I.L.; CHAN,P.H.I.L.; ISCHENKO,A.L.E.X.; BRADY,JENNIFER J.; FONTAINE,M.A.R.C.
FASEB Journal 2003;17:1003-1014.
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Abstract
C3a and C5a anaphylatoxins are cytokine-like polypeptides generated during complement (C) system activation and released at the inflammatory site. They exert several biological activities through binding to the G-protein-coupled receptors C3aR and C5aR, respectively. Cloning and Northern blot experiments have indicated that both receptors are expressed by myeloid as well as nonmyeloid cells (e.g., endothelial and epithelial cells). To better understand the roles of C anaphylatoxins during inflammation, we investigated their effects on the expression of cytokine and chemokine genes by cultured human umbilical cord endothelial cells (HUVEC). HUVEC constitutively expressed both anaphylatoxin receptors, and addition of physiological concentrations of C3a or C5a (nM range) caused a strong up-regulation of IL-8, IL-1{beta}, and RANTES mRNA in a time- and dose-dependent manner. Conversely, a decrease in IL-6 mRNA was observed, but only with C5a stimulation. These variations in mRNA levels were inhibited by pretreatment with anti-C5aR and anti-C3aR antibodies as well as pertussis toxin, indicating that G-proteins are involved in anaphylatoxin-activated signal transduction pathways. Finally, we showed that C3a and C5a both strongly activate downstream MAP kinase signaling pathways (p44 and p42 Erk kinases).--Monsinjon, T., Gasque, P., Chan, P., Ischenko, A., Brady, J.J., Fontaine, M. Regulation by complement C3a and C5a anaphylatoxins of cytokine production in human umbilical vein endothelial cells
47
Lipid metabolism and TNF-alpha secretion in response to dietary sterols in human monocyte derived macrophages
Napolitano,M.; Bravo,E.
European Journal of Clinical Investigation 2005;35:482-490.
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Abstract
Abstract Background The postprandial phase is characterized by the circulation of atherogenic dietary-triacylglycerol rich lipoproteins. Little is known about the modulation of lipid and immune functions in macrophages by these particles or of the role of the oxysterols found in food such as 7beta-hydroxycholesterol and 7-ketocholesterol. Materials and methods Human macrophages were tested with different concentrations of chylomicron remnant-like particles (CRLP) with or without incorporated oxysterols to study their uptake by the cells, and their effects on cholesteryl ester and triacylglycerol synthesis and the secretion of inflammatory mediators, including tumour necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6) and interleukin 10 (IL-10). Results Independently of the presence of oxysterols, CRLP caused cholesterol accumulation. However, the dose-dependent increase in [3H]cholesterol internalization by macrophages after incubation with [3H]cholesteryl ester-labelled CRLP was abolished by the presence of oxysterols in the particles. TNF-alpha secretion was decreased and that of IL-10 unaffected by CRLP independently of the presence of oxysterol. Exposure to CRLP containing 7beta-hydroxysterol, but not to CRLP or 7-ketosterol-containing CRLP, reduced IL-6 secretion with respect to cells not exposed to any particles. Because TNF-alpha levels have been related to scavenger receptor expression, we tested the uptake of modified LDL in macrophages exposed to human postprandial triacylglycerol-rich lipoproteins and found it to be markedly increased. Conclusions Cholesterol loading as a result of dietary lipids depresses the inflammatory response of macrophages and the presence of 7beta-hydroxysterol may exacerbate this effect. In addition, exposure to dietary lipids enhances scavenger receptor activity in macrophages. These results suggest that changes induced by dietary lipids in human macrophage function are related to an increased propensity of the cells to accumulate lipids during the postprandial phase. Eur J Clin Invest 2005; 35 (8): 482 -490
626
Endurance training reduces circulating inflammatory markers in persons at risk of coronary events: Impact on plaque..
Niessner,A.; Richter,B.; Penka,M.; Steiner,S.; Strasser,B.; Ziegler,S.; Heeb-Elze,E.; Zorn,G.; Leitner-Heinschink,A.; Niessner,C.
Atherosclerosis 2006;186:160-165.
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Abstract
Inflammatory pathways are involved in destabilization of atherosclerotic plaques. We assessed the hypothesis that endurance training decreases circulating concentrations of inflammatory markers in persons with coronary artery disease (CAD) and cardiovascular risk factors (CVRFs). Thirty-two subjects with CAD and/or CVRFs joined a 12-week supervised endurance training. We found a significant decrease of the chemokines interleukin (IL)-8 (pre: 3.9 ± 0.6, change: -1.2 ± 0.4 pg/ml, -21%, p = 0.002) and monocyte chemoattractant protein-1 (pre: 213 ± 9, change: -20.4 ± 8.2 pg/ml, -5%, p = 0.03). Diabetes mellitus (DM) significantly influenced changes of IL-8 (p = 0.002). IL-8 substantially dropped by 39% in diabetics. Moreover, matrix metalloproteinase-9 (MMP-9) highly significantly decreased in response to training (pre: 750 ± 98, change: -278 ± 77 ng/ml, -18%, p = 0.005). Exercise-induced changes of MMP-9 were influenced by concomitant use of statins (p = 0.038). We observed a particularly strong MMP-9 reduction of 44% in patients treated with statins. Acute phase reactants IL-6 (pre: 1.7 ± 0.3, change: +0.25 ± 0.7 pg/ml, +4%, p = 0.58) and high sensitivity C-reactive protein (pre: 2.1 ± 0.5, change: -0.25 ± 0.4 mg/l, -9%, p = 0.54) did not change in response to training. In conclusion, endurance training decreased circulating chemokines and MMP-9, which may in part explain its beneficial effect on coronary risk. Patients with DM or treated with statins because of hypercholesterolemia may particularly take advantage.
1032
Signaling Through a CD3{gamma}-Deficient TCR/CD3 Complex in Immortalized Mature CD4+ and CD8+ T Lymphocytes
Pacheco-Castro,Alberto; Alvarez-Zapata,David; Serrano-Torres,Pilar; Regueiro,Jose R.
The Journal of Immunology 1998;161:3152-3160.
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Abstract
The biologic role of each CD3 chain and their relative contribution to the signals transduced through the TCR/CD3 complex and to downstream activation events are still controversial: they may be specialized or redundant. We have immortalized peripheral blood CD4+ and CD8+ T lymphocytes from a human selective CD3{gamma} deficiency using Herpesvirus saimiri. The accessibility of the mutant TCR/CD3 complex to different Abs was consistently lower in immortalized CD8+ cells when compared with CD4+ cells, relative to their corresponding CD3{gamma}-sufficient controls. Several TCR/CD3-induced downstream activation events, immediate (calcium flux), early (cytotoxicity and induction of surface CD69 or CD40L activation markers or intracellular TNF-{alpha}) and late (proliferation and secretion of TNF-{alpha}), were normal in {gamma}-deficient cells, despite the fact that their TCR/CD3 complexes were significantly less accessible than those of controls. In contrast, the accumulation of intracellular IL-2 or its secretion after CD3 triggering was severely impaired in {gamma}-deficient cells. The defect was upstream of protein kinase C activation because addition of transmembrane stimuli (PMA plus calcium ionophore) completely restored IL-2 secretion in {gamma}-deficient cells. These results suggest that the propagation of signals initiated at the TCR itself can result in a modified downstream signaling cascade with distinct functional consequences when {gamma} is absent. They also provide evidence for the specific participation of the CD3{gamma} chain in the induction of certain cytokine genes in both CD4+ and CD8+ human mature T cells. These immortalized mutant cells may prove to be useful in isolating cytosolic signaling pathways emanating from the TCR/CD3 complex
293
Intermittent high glucose enhances ICAM-1, VCAM-1, E-selectin and interleukin-6 expression in human umbilical endothelial cells in culture: the role of poly(ADP-ribose) polymerase
Piconi,L.; Quagliaro,L.; Da Ros,R.; Assaloni,R.; Giugliano,D.; Esposito,K.; Szabo,C.; Ceriello,A.
Journal of Thrombosis and Haemostasis 2004;2:1453-1459.
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Abstract
Summary. It has been previously reported that endothelial cells exposed to constant high concentrations of glucose upregulate the expression of adhesion molecules. Moreover, it has been suggested that this phenomenon is related to generation of oxidative stress. It has also been suggested that oxidative injuries, related to high glucose, induce the activation of the enzyme poly ADP ribose polymerase (PARP), which can promote the expression of adhesion molecules and the generation of inflammation. Recent in-vivo and in-vitro evidence suggests that oscillation of glucose may play an autonomous and direct role in favoring the development of cardiovascular complications in diabetes. In this study we have investigated the effects of constantly high and intermittently high glucose on nitrotyrosine formation (a marker of nitrosative stress) and adhesion molecule (ICAM-1, VCAM-1 and E-selectin), as well as on interleukin (IL)-6 expression in human umbilical vein endothelial cells, either in the presence or in the absence of PJ34, a potent inhibitor of PARP. We found that oscillating glucose was more effective in triggering the generation of nitrotyrosine and inducing the expression of adhesion molecules and IL-6 than stable high glucose. Pharmacological inhibition of PARP suppressed both nitrotyrosine formation, adhesion molecule expression and IL-6 to the levels seen in the normal glucose conditions. Thus, PARP activation appears to be involved in both promoting nitrosative stress and upregulating adhesion molecules and inflammation in endothelial cells exposed to oscillating high glucose conditions
621
Exaggerated apoptosis and NF-{kappa}B activation in pancreatic and tracheal cystic fibrosis cells
Rottner,Mathilde; Kunzelmann,Corinne; Mergey,Martine; Freyssinet,Jean Marie; Martinez,Maria Carmen
FASEB Journal 2007;fj› Link
Abstract
The pathophysiologic mechanisms causing inflammation in cystic fibrosis (CF) remain obscure. The effects of proapoptotic agents on pancreatic and tracheal cell lines expressing wild-type CFTR (PANC-1 and NT-1, respectively) or the homozygous CFTR{Delta}F508 mutation (CFPAC-1 and CFT-2, respectively) were assessed. An increased susceptibility to apoptosis was observed in CFPAC-1 and CFT-2 cells. Apoptosis was reduced by treatment with a pan-caspase inhibitor and by incubation at 27{degrees}C, allowing recruitment of CFTR{Delta}F508 at the plasma membrane. Inhibition of CFTR function in wild-type cells induced an increase of apoptosis. Apoptosis in CFPAC-1, but not in CFT-2 cells, was associated with overexpression of the proinflammatory mediators interleukin-6 and interleukin-8. In CF cells, apoptosis was linked to NF-{kappa}B pathway activation. Conditioned medium from actinomycin D-treated CFPAC-1 cells produced an increase in apoptosis of wild-type cells, suggesting that proinflammatory mediators secreted by mutant cells promote apoptosis. This was confirmed through the induction of apoptosis in wild-type cells by exogenous interleukin-6 and interleukin-8. These results suggest that CFTR{Delta}F508 mutation, apoptosis, and activation of the NF-{kappa}B pathway contribute to the self-perpetuating inflammatory cycle, at least in pancreatic cells, and provide evidence that excessive apoptosis may account for the exaggerated proinflammatory response observed in CF patients.--Rottner, R., Kunzelmann, C., Mergey, M., Freyssinet, J-M., Martinez, M. C. Exaggerated apoptosis and NF-{kappa}B activation in pancreatic and tracheal cystic fibrosis cells
851
Oxidized Low-Density Lipoprotein Augments and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Limit CD40 and CD40L Expression in Human Vascular Cells
Schonbeck,Uwe; Gerdes,Norbert; Varo,Nerea; Reynolds,Rebecca S.; Horton,Daniel B.; Bavendiek,Udo; Robbie,Linda; Ganz,Peter; Kinlay,Scott; Libby,Peter
Circulation 2002;106:2888-2893.
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Abstract
Although CD40 signaling participates in atherosclerosis, links between lipid risk factors and this inflammatory pathway remain obscure. Cardiovascular risk reduction by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may involve actions beyond lipid lowering, including reduced inflammation. Therefore, this study analyzed whether oxidized low-density lipoprotein (oxLDL) induces CD40/CD40L expression on cells implicated in atherogenesis and whether statins affect their expression in vitro as well as the expression of soluble CD40L (sCD40L) in vivo. Methods and Results-- Treatment of human vascular endothelial and smooth muscle cells and mononuclear phagocytes with oxLDL augmented the basal expression of CD40 and CD40L mRNA and protein. In contrast, cerivastatin, atorvastatin, or simvastatin concentration-dependently diminished the constitutive as well as oxLDL- or cytokine-induced expression of the receptor/ligand dyad, an effect reversed by mevalonate. Patients treated with statins had diminished sCD40L plasma levels compared with untreated control patients (8.3{+/-}3.1 ng/mL [n=11] versus 13.1{+/-}2.5 ng/mL [n=16], P<0.05), supporting the clinical relevance of the in vitro observations. Platelet-enriched plasma of mice deficient in CD40L showed markedly delayed fibrin clot formation, suggesting a role for the ligand in blood coagulation and supporting the hypothesis that statin-mediated reduction in CD40/CD40L expression might limit thrombosis. Conclusions-- OxLDL may promote expression of CD40 and CD40L in human atheroma. Statins may limit the expression of the CD40 receptor/ligand dyad in two ways, directly as well as through diminished lipoprotein levels. Thus, reduced CD40 signaling may account for some of the statins' antiinflammatory action.
864
Polymorphonuclear leucocytes selectively produce anti-inflammatory interleukin-1 receptor antagonist and chemokines, but fail to produce pro-inflammatory mediators
Schroder,Anja K.; von der Ohe,Maren; Kolling,Ute; Altstaedt,Julia; Uciechowski,Peter; Fleischer,Daniela; Dalhoff,Klaus; Ju,Xinsheng; Zenke,Martin; Heussen,Nicole; Rink,Lothar
Immunology 2006;119:317-327.
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Abstract
Summary The role of neutrophils in the immune response has long been regarded as mainly phagocytic, but recent publications have indicated the production of several cytokines by polymorphonuclear leucocytes (PMN). The results of the individual reports, however, vary considerably. In this study, we established a cytokine profile of pure human neutrophils and demonstrated that minor contamination of peripheral blood mononuclear cells (PBMCs) in PMN preparations can lead to false-positive results. In our hands, peripheral blood PMN fail to produce the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha). Instead, they secrete large amounts of the chemokine IL-8 and the anti-inflammatory IL-1 receptor antagonist (IL-1ra). Additionally, PMN preparations of a high purity show production of the chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and growth-related oncogene-alpha (GRO-alpha), as well as macrophage colony-stimulating factor (M-CSF). The neutrophil therefore represents a novelty by producing the antagonist of IL-1beta (i.e. IL-1ra) in the absence of IL-1beta itself. To support our results, we differentiated stem cells from human cord blood into PMN and monocytes, respectively. These in vitro-differentiated PMN showed the same cytokine profile as peripheral blood PMN lacking IL-1beta, while differentiated monocytes produced the expected IL-1beta in addition to IL-1ra. The clear anti-inflammatory nature of their cytokine profile enables PMN to antagonize pro-inflammatory signals in experimental conditions. It is therefore possible that PMN play a key role in immune regulation by counteracting a dysregulation of the inflammatory process. Clinical studies, in which administration of recombinant G-CSF had a favourable effect on the outcome of severe infections and even sepsis without worsening inflammation, could thus be explained by our results
1417
Increased insulin-stimulated endothelin-1 release is a distinct vascular phenotype distinguishing Cushing's disease from metabolic syndrome
Setola,Emanuela; Losa,Marco; Lanzi,Roberto; Lucotti,Pietro; Monti,Lucilla D.; Castrignano,Tristana; Galluccio,Elena; Giovanelli,Massimo; Piatti,PierMarco
Clinical Endocrinology 2007;66:586-592.
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Abstract
Summary Objective Although much is known about the anti-inflammatory effects of an acute corticosteroid therapy, little is known about the effects on chronic hypercortisolism on endothelial dysfunction and proinflammatory alterations in patients with Cushing's disease (CD). Patients and methods We studied 9 patients with CD, 10 patients with metabolic syndrome and 27 normal controls. The tests consisted of an intravenous bolus of 0.1 U/kg insulin combined with a euglycaemic clamp technique with an arterialized forearm and assessment of the training parameters deep-venous balance of forearm glucose uptake (as an index of insulin sensitivity); NOx (nitric oxide end-products), c-GMP (second messenger of nitric oxide) and endothelin-1 release, as indices of endothelial function and proinflammatory systemic markers. Results Forearm glucose uptake incremental area was significantly lower in Cushing's disease and in the metabolic syndrome than in controls, suggesting a state of severe insulin resistance. Compared to controls and to the metabolic syndrome, basal and insulin-stimulated NOx release incremental areas were significantly reduced in Cushing's disease, while forearm c-GMP release was similarly decreased in CD and metabolic syndrome. By contrast, endothelin-1 incremental areas after insulin bolus were significantly higher in CD than in controls and the metabolic syndrome, in the presence of increased TNF-alpha, IL-6 and CRP levels. Forearm glucose uptake incremental area significantly correlated with NOx incremental area, forearm c-GMP release incremental area, TNF-alpha levels and ET-1 incremental area. Conclusions In patients with CD, supraphysiological insulin levels are not able to overcome the insulin resistance due to chronic hypercortisolism. Furthermore, an increased proatherogenic risk profile is characterized by decreased nitric oxide synthesis and activity, enhanced endothelin-1 levels and increased proinflammatory markers
1419
Inflammatory Markers and Cardiovascular Risk in Healthy Polish Women across the Menopausal Transition
Stefanska,Anna; Sypniewskay,Grazyna; Senterkiewicz,Lilla
Clinical Chemistry 2005;51:1893-1895.
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Abstract
Cessation of ovarian function and sex hormone deficiency are associated with metabolic disorders that increase the risk of cardiovascular disease in women after menopause (1)(2). Changes in sex steroids may influence inflammatory processes and lipid metabolism during the menopausal transition. The status of estrogen in women at early perimenopause is similar to that of premenopause, whereas decreased estradiol is more likely in late perimenopause (3-11 months of amenorrhea) (3). Several studies have demonstrated that lipid concentrations, body weight, blood pressure, and insulin resistance increase after menopause and that endothelial function is impaired (4)(5)(6)(7). Recent data indicate that chronic inflammation may lead to atherosclerosis in healthy populations. It has been suggested that systemic markers of inflammation such as C-reactive protein (CRP) and interleukin-6 (IL-6) are important predictors of cardiovascular risk, and measurement of their concentrations may increase the predictive value of traditional lipid screening (8)(9). CRP assayed by high-sensitivity methods enables the evaluation of low-grade inflammation in early atherosclerosis. Rifai et al. (10)(11) recently proposed algorithms for the prediction of cardiovascular disease risk using CRP and total cholesterol/HDL-cholesterol (TC/HDL-C) or LDL-cholesterol (LDL-C) values.
523
Pro- and anti-inflammatory cytokines in the CSF of patients with Creutzfeldt-Jakob disease
Stoeck,K.; Bodemer,M.; Zerr,I.
Journal of Neuroimmunology 2006;172:175-181.
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Abstract
We investigated cerebrospinal fluid (CSF) samples from patients with Creutzfeldt-Jakob disease (CJD) and other neurological diseases. Concentrations of pro- and anti-inflammatory cytokines IL-1ß, IL-6, IL-8, IL-12, TNF-a and TGF-ß 2 were determined in CSF using ELISA. Significant changes were found for IL-8 and TGF-ß 2. IL-8 levels were elevated in the CSF of CJD patients. Of interest, the increase was significant to other dementia and to controls. In contrast, TGF-ß 2 was significantly decreased in CSF of CJD compared to all groups. IL-1ß, IL-12 and TNF-a could not be detected in CSF or in case of IL-6 in only low concentrations without significant difference.
1084
Activation of Tubular Epithelial Cells in Diabetic Nephropathy and the Role of the Peroxisome Proliferator-Activated Receptor-{gamma} Agonist
Tang,Sydney C.W.; Leung,Joseph C.K.; Chan,Loretta Y.Y.; Tsang,Anita W.L.; Lai,Kar Neng
Journal of the American Society of Nephrology 2006;17:1633-1643.
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Abstract
The effects of advanced glycation end products (AGE) in the form of glycated albumin (GA) on the proinflammatory phenotype of cultured renal proximal tubular epithelial cells (PTEC) and the therapeutic potential of the peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) agonist were studied. Human PTEC were exposed to medium alone or supplemented with albumin or GA with or without previous addition of rosiglitazone (0.1 to 0.5 {micro}M). Exposure to GA (up to 0.5 mg/ml) but not the equivalent dose of neat albumin significantly upregulated both mRNA and protein expression of IL-8 and soluble intercellular adhesion molecule-1 (sICAM-1) in a dose- and time-dependent manner. Using immunohistochemistry, ICAM-1 signals were detected in the tubular epithelia and peritubular capillaries in association with AGE deposition and leukocyte infiltration, whereas IL-8 staining was localized in the tubular epithelia of human diabetic kidney biopsies. Also in a dose-dependent manner, GA (0.5 mg/ml) but not albumin caused nuclear translocation of NF-{kappa}B and activation of mitogen-activated protein kinase (MAPK) p44/p42 and signal transducer and activator of transcription (STAT-1). Inhibition of these pathways with pyrrolidine dithiocarbamate, PD 98059, and fludarabine, respectively, attenuated GA-induced IL-8 secretion. Rosiglitazone dose-dependently attenuated GA-induced IL-8 and ICAM-1 signals in PTEC and completely abolished GA-induced STAT-1 signals but had no effect on NF-{kappa}B and MAPK activation. These findings suggest that AGE stimulate renal tubular expression of adhesion molecule and chemokine that together may account for the transmigration of inflammatory cells into the interstitial space during diabetic tubulopathy. Such proinflammatory phenotype may be partially modified by PPAR-{gamma} ligation through STAT-1 inhibition independent of NF-{kappa}B transcriptional activity and MAPK signaling
757
Elevated Levels of Interleukin-6 in Young Adults With Type 1 Diabetes Without Clinical Evidence of Microvascular and Macrovascular Complications
Targher,Giovanni; Zenari,Luciano; Bertolini,Lorenzo; Muggeo,Michele; Zoppini,Giacomo
Diabetes Care 2001;24:956-957.
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Abstract
The past decade has been characterized by growing interest in the idea that atherosclerosis is an inflammatory disease, and by the finding that serum levels of markers of inflammation can be used to predict the risk of cardiovascular events (1). Elevated concentrations of acute-phase reactants, such as C-reactive protein, soluble intercellular adhesion molecule-1, and fibrinogen, are found in patients with acute coronary syndromes and are predictors of future risk in apparently healthy individuals (123). The inflammatory cytokine interleukin-6 (IL-6) is a powerful inducer of the hepatic acute-phase response, and it has been proposed to be a central mediator in the pathogenesis of coronary heart disease through a combination of autocrine, paracrine, and endocrine mechanisms (4). In fact, in a recent study, serum levels of IL-6 were predictive of the risk of myocardial infarction in apparently healthy individuals, and although the levels of IL-6 were strongly correlated with the levels of C-reactive protein, the association between IL-6 and the risk of myocardial infarction remained significant, even after adjustment for the C-reactive protein level (5).
179
Ketamine Modulates the Stimulated Adhesion Molecule Expression on Human Neutrophils In Vitro
Weigand,Markus A.; Schmidt,Heinfried; Zhao,Qingyu; Plaschke,Konstanze; Martin,Eike; Bardenheuer,Hubert J.
Anesthesia & Analgesia 2000;90:206› Link
Abstract
Cytokine production, neutrophil adhesion to endothelial cells, and release of reactive oxygen species are thought to be critical events in sepsis or ischemia/reperfusion. Modulation of leukocyte responses by anesthetics may have an important role in limiting tissue injury under these conditions. Therefore, we investigated the effect of ketamine on the expression of CD18, CD62L, and oxygen radical production of human neutrophils in vitro and on interleukin-6 production in endotoxin-stimulated human whole blood. Ketamine inhibited both the N- formyl-methionyl-leucyl-phenylalanine- and phorbol 12-myristate 13-acetate-induced up-regulation of CD18 and shedding of CD62L, determined by flow cytometry, in a concentration-dependent manner. Ketamine also caused a significant suppression of oxygen radical generation of isolated human neutrophils. In addition, there was a significant decrease in endotoxin-stimulated interleukin-6 production in human whole blood. The inhibitory effects were similar for racemic ketamine and its isomers S(+)-ketamine and R(-)-ketamine, suggesting that the inhibition of stimulated neutrophil function is most likely not mediated through specific receptor interactions. Implications: Modulation of leukocyte responses by anesthetics may have an important role in limiting tissue injury in sepsis or ischemia/reperfusion. Therefore, we examined the effect of ketamine on stimulated neutrophil functions in vitro. These neutrophil functions were significantly inhibited by ketamine, independent of whether the racemic mixture or isomers were tested
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Mobilization of CD34/CXCR4+, CD34/CD117+, c-met+ Stem Cells, and Mononuclear Cells Expressing Early Cardiac, Muscle, and Endothelial Markers Into Peripheral Blood in Patients With Acute Myocardial Infarction
Wojakowski,Wojciech; Tendera,Michal; Michalowska,Anna; Majka,Marcin; Kucia,Magdalena; Maslankiewicz,Katarzyna; Wyderka,Rafal; Ochala,Andrzej; Ratajczak,Mariusz Z.
Circulation 2004;110:3213-3220.
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Abstract
Background-- Adult stem cells can contribute to myocardial regeneration after ischemic injury. Bone marrow and skeletal muscles contain a population of CXCR4+ cells expressing genes specific for muscle progenitor cells that can be mobilized into the peripheral blood. The aims of the study were (1) to confirm the presence of early tissue-committed cells expressing cardiac, muscle, and endothelial markers in populations of mononuclear cells in peripheral blood and (2) to assess the dynamics and magnitude of the mobilization of CD34+, CD117+, CXCR4+, c-met+, CD34/CD117+, and CD34/CXCR4+ stem cells into peripheral blood in relation to inflammatory and hematopoietic cytokines in patients with ST-segment-elevation acute myocardial infarction (STEMI). Methods and Results-- Fifty-six patients with STEMI (<12 hours), 39 with stable angina, and 20 healthy control subjects were enrolled. Real-time reverse transcription-polymerase chain reaction (RT-PCR) was used for detection of tissue-specific markers. The number of the cells was assessed by use of a flow cytometer on admission, after 24 hours, and after 7 days. RT-PCR revealed increased expression of mRNA (up to 3.5-fold increase) for specific cardiac (GATA4, MEF2C, Nkx2.5/Csx), muscle (Myf5, Myogenin, MyoD), and endothelial (VE-cadherin, von Willebrand factor) markers in peripheral blood mononuclear cells. The number of CD34/CXCR4+ and CD34/CD117+ and c-met+ stem cells in peripheral blood was significantly higher in STEMI patients than in stable angina and healthy subjects, peaking on admission, without further significant increase after 24 hours and 7 days. Conclusions-- The study demonstrates in the setting of STEMI a marked mobilization of mononuclear cells expressing specific cardiac, muscle, and endothelial markers as well as CD34/CXCR4+ and CD34/CD117+ and c-met+ stem cells and shows that stromal cell-derived factor-1 is an important factor influencing the mobilization
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Mobilization of CD34+, CD117+, CXCR4+, c-met+ stem cells is correlated with left ventricular ejection fraction and plasma NT-proBNP levels in patients with acute myocardial infarction
Wojakowski,Wojciech; Tendera,Michal; Zebzda,Anna; Michalowska,Anna; Majka,Marcin; Kucia,Magdalena; Maslankiewicz,Katarzyna; Wyderka,Rafal; Krol,Marek; Ochala,Andrzej; Kozakiewicz,Krystyna; Ratajczak,Mariusz Z.
European Heart Journal 2006;27:283-289.
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Abstract
Aims The aim of the study was to assess the correlation between the number of CD34+, CD117+, c-met+, CXCR4+ stem cells mobilized into peripheral blood, left ventricular ejection fraction (LVEF), NT-proBNP levels, and myocardial necrosis markers in patients with acute myocardial infarction (AMI). Methods and results 43 patients with STEMI were enrolled. Stem cells number was measured using flow-cytometer and concentrations of NT-proBNP, SDF-1, G-CSF, VEGF, IL-6, and HGF were measured using ELISA kits. The number of stem cells mobilized early (<12 h) in AMI was significantly, positively correlated with LVEF: r=0.49 (P=0.0012) for CD34+ cells, r=0.48 (P=0.0018) for CXCR4+ cells, r=0.45 (P=0.0043) for CD117+ cells, and r=0.41 (P=0.01) for c-met+ cells and negatively correlated with NT-proBNP levels on admission r=-0.35 (P=0.024) for CD34+ cells, r=-0.42 (P=0.007) for CXCR4+ cells, r=-0.33 (P=0.04). In patients with LVEF [≤]40%, the peak number of CD34+, CXCR4+, CD117+, and c-met+ stem cells was significantly lower when compared patients with LVEF >40%. The number of CXCR4+ cells on admission and after 24 h was negatively correlated with respective cardiac Troponin I levels (r=-0.37; P=0.029 and r=-0.45, P=0.02) and maximum activity of CK-MB (r=-0.37; P=0.021). No significant correlations between levels of haematopoietic cytokines and LVEF were found. Conclusion The mobilization of CD34+, CD117+, CXCR4+, c-met+ stem cells into peripheral blood early in STEMI is positively correlated with LVEF and negatively correlated with NT-proBNP levels and myocardial necrosis markers
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