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
Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma
Breitkreutz,I.; Raab,M.; Vallet,S.; Hideshima,T.; Raje,N.; Mitsiades,C.; Chauhan,D.; Okawa,Y.; Munshi,N.; Richardson,P.; Anderson,K.
Leukemia 2008;22:1925-1932.
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Abstract
Osteolytic bone disease in multiple myeloma (MM) is caused by enhanced osteoclast (OCL) activation and inhibition of osteoblast function. Lenalidomide and bortezomib have shown promising response rates in relapsed and newly diagnosed MM, and bortezomib has recently been reported to inhibit OCLs. We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis in comparison with bortezomib. Both drugs decreased V3-integrin, tartrate-resistant acid phosphatase-positive cells and bone resorption on dentin disks. In addition, both agents decreased receptor activator of nuclear factor-B ligand (RANKL) secretion of bone marrow stromal cells (BMSCs) derived from MM patients. We identified PU.1 and pERK as major targets of lenalidomide, and nuclear factor of activated T cells of bortezomib, resulting in inhibition of osteoclastogenesis. Furthermore, downregulation of cathepsin K, essential for resorption of the bone collagen matrix, was observed. We demonstrated a significant decrease of growth and survival factors including macrophage inflammatory protein-, B-cell activating factor and a proliferation-inducing ligand. Importantly, in serum from MM patients treated with lenalidomide, the essential bone-remodeling factor RANKL, as well as the RANKL/OPG ratio, were significantly reduced, whereas osteoprotegerin (OPG) was increased. We conclude that both agents specifically target key factors in osteoclastogenesis, and could directly affect the MM-OCL-BMSCs activation loop in osteolytic bone disease.
2274
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.
914
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
BMP-7 protects mesangial cells from injury by polymeric IgA
Chan,Wai Long; Leung,Joseph; Chan,Loretta; Tam,K.; Tang,Sydney; Lai,Kar Neng
Kidney Int 2008;74:1026-1039.
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Abstract
Bone morphogenetic protein-7 (BMP-7) is a potential therapeutic agent for acute and chronic renal diseases. Here we found that addition of polymeric IgA, isolated from patients with IgA nephropathy, increased the synthesis of tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), transforming growth factor-b (TGF-b) and fibronectin in cultured human mesangial cells, effects blunted by BMP-7. When mesangial cells were cultured with both polymeric IgA and BMP-7 there was an increase in the expression of peroxisome proliferator-activated receptor-g (PPAR-g). The activation of NFkB and TNF-a synthesis induced by polymeric IgA or TNF-a were downregulated by BMP-7 or rosiglitazone. BMP-7 inhibited TNF-a release from polymeric IgA-stimulated mesangial cells by activation of PPAR-g but suppressed TGF-b release by mechanisms independent of PPAR-g. The expression of inhibitory Smad6 and 7 was increased whereas the expression of active Smad2 and 3 was reduced in these mesangial cells by BMP-7. Our study shows that BMP-7 ameliorates IgA nephropathy-derived polymeric IgA-induced TNF-a and TGF-b synthesis in human mesangial cells through multiple mechanisms involving inhibitory Smads and PPAR-g.
2269
Identification and characterization of oligonucleotides that inhibit Toll-like receptor 2-associated immune responses
Chang,Yi Chung; Kao,Wei Chen; Wang,Wei Ya; Wang,Wan Yi; Yang,Ruey Bing; Peck,Konan
FASEB Journal 2009;fj› Link
Abstract
Toll-like receptors (TLRs) play important roles in the immune responses against invading microorganisms. Development of TLR antagonists is recognized as a promising direction in suppressing the associated inflammatory reactions of the TLRs. Aptamers are single-stranded RNA or DNA molecules isolated through an in vitro selection process. Using a novel molecular evolution strategy that combines immunoprecipitation (IP) with systematic evolution of ligands by exponential enrichment (SELEX), we developed an IP-SELEX selection method to facilitate the screening of high-affinity aptamers for the Toll-like receptor 2 (TLR2). Also, human TLR2 functional aptamers were identified and characterized using NF-{kappa}B reporter assays. Among the functional aptamers, the most effective, AP177, with a dissociation constant of 73 pM, was characterized with TLR2-expressing cells challenged with bacterial cells and purified ligands. The aptamer could effectively antagonize TLR2, significantly inhibit NF-{kappa}B activity, and suppress the secretion of the cytokines by >80%. In addition, the precise region within the functional aptamer that specifically bound TLR2 was resolved using aptamer microarray analysis. The results of functional assays showed that AP177 acted as a TLR2 antagonist and may hold therapeutic potential in the treatment of diseases related to dysregulated TLR2 immune responses.
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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
378
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
617
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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Home use of vegetable oils, markers of systemic inflammation, and endothelial dysfunction among women
Esmaillzadeh,Ahmad; Azadbakht,Leila
American Journal of Clinical Nutrition 2008;88:913-921.
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Abstract
Background: Most knowledge about adverse health effects of trans fats was mainly derived from studies done in Western populations of European or American origins; few data are available in the understudied region of the Middle East. Objective: We assessed the association between consumption of partially hydrogenated vegetable oils (PHVOs) and non-HVOs and circulating concentrations of inflammatory markers among Tehrani women aged 40-60 y. Design: Usual dietary intakes were assessed with a food-frequency questionnaire among 486 apparently healthy women. PHVOs (commonly used for cooking in Iran) were considered as PHVOs category. Sunflower oil, corn oil, canola oil, soybean oil, and olive oil were defined as non-HVOs. Anthropometric measurements were done, and fasting blood samples were taken to measure inflammatory markers. Results: The energy-adjusted daily intakes (mean {+/-} SD) of PHVOs and non-HVOs were 23 {+/-} 11 and 22 {+/-} 10 g/d, respectively. After control for potential confounders, women in the highest quintile of PHVO intake had higher plasma concentrations of C-reactive protein (CRP; percentage difference from lowest quintile: 45%; P for trend: <0.01), tumor necrosis factor-{alpha} (TNF-{alpha}; 66%; P for trend: <0.01), interleukin-6 (72%; P for trend: <0.05), and soluble intercellular adhesion molecule-1 (sICAM-1; 22%; P for trend: <0.01) than did women in the lowest quintile. In contrast, higher consumption of non-HVOs was associated with lower circulating concentrations of CRP (percentage difference between top and bottom quintiles: -23%; P for trend: 0.05), TNF-{alpha} (-29%; P for trend: <0.01), serum amyloid A (-24%; P for trend: <0.01), and sICAM-1 (-19%; P for trend:<0.05). Adjustment for body mass index, fasting plasma glucose, and lipid profiles slightly attenuated the associations in some cases. Conclusions: Higher intakes of PHVOs are associated with elevated concentrations of inflammatory biomarkers, whereas higher intakes of non-HVOs are associated with lower plasma concentrations of these biomarkers
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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
Association of device surface and biomaterials with immunologic sensitization after mechanical support
George,Isaac; Colley,Patrick; Russo,Mark J.; Martens,Timothy P.; Burke,Elizabeth; Oz,Mehmet C.; Deng,Mario C.; Mancini,Donna M.; Naka,Yoshifumi
The Journal of Thoracic and Cardiovascular Surgery 2008;135:1372-1379.
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Abstract
Objective Biomaterials and textured surfaces in early pulsatile left ventricular assist devices (HeartMate I; Thoratec Corporation, Pleasanton, Calif) may increase immunologic risk through allosensitization. We hypothesized that axial-flow devices without biologic membranes or textured surfaces (HeartMate II; Thoratec; and DeBakey; MicroMed Cardiovascular, Inc, Houston, Tex) would cause less allosensitization than devices with such membranes and surfaces.Methods HeartMate II and DeBakey (n = 24) and HeartMate I (n = 36) devices were implanted from 1999 to 2006 in patients with severe heart failure cohort-matched for age, etiology, and support duration. Serum samples reacting with more than 10% of the HLA reference panel were considered positive for anti-HLA antibodies. Endomyocardial biopsy samples were collected after transplant.Results There were no significant cohort differences in age, etiology, sex, blood transfusion, or support duration. Anti-HLA antibodies were not detected at implantation of either HeartMate II and DeBakey or HeartMate I devices; however, significant increases in anti-HLA antibodies were present within 1 and 3 months of support with HeartMate I but not HeartMate II and DeBakey devices. Overall, fewer patients with HeartMate II and DeBakey devices demonstrated positive anti-HLA antibodies during support (8% vs 28%, P = .02), and fewer episodes of acute rejection per patient were seen within the first 9 posttransplant months(0.31 vs 0.69, P = .052). Long-term posttransplant survival was not different between groups.Conclusion Hemodynamic support with HeartMate II and DeBakey devices produced less allosensitization than did HeartMate I devices. Device selection may improve clinical outcomes for high-risk patients.
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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
Obesity reduces the bioavailability of nitric oxide in juveniles
Gruber,H.J.; Mayer,C.; Mangge,H.; Fauler,G.; Grandits,N.; Wilders-Truschnig,M.
Int.J.Obes.(Lond) 2008;32:826-831.
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Abstract
OBJECTIVE: There is growing evidence that nitric oxide (NO) is critically involved in obesity and its clinical consequences like cardiovascular disease, hypertension and diabetes. We hypothesize that NO is already involved in the pathophysiology of juvenile obesity. We here determined the role of NO, its metabolites arginine and citrulline in obese and normal weight children. DESIGN: We investigated 57 obese and 57 normal weight age- and gender-matched juveniles. Various clinical parameters as well as body measurements and intima media thickness were determined. RESULTS: Obese juveniles revealed highly significant alterations in the NO pathway. NOX and citrulline were decreased in obese compared to normal weight juveniles and negatively correlated with body weight. Arginine was increased in obese juveniles and positively correlated with body weight. We found a significant negative correlation between NOX and oxidized low-density lipoprotein. Analysis of gamma-aminobutyric acid (GABA) revealed correlations with the NO pathway as NOX and citrulline were negatively correlated with GABA and arginine showed a positive correlation. CONCLUSION: We show here that NO and its metabolites arginine and citrulline are already involved in juvenile obesity that may contribute to atherogenesis via reduced bioavailability of NO. Moreover, we identify GABA as a new parameter in the mechanism of obesity-related NO reduction
1330
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
107
Alterations in the number of circulating leucocytes, phenotype of monocyte and cytokine production in patients undergoing cardiothoracic surgery
HIESMAYR,M.J.; SPITTLER,A.; LASSNIGG,A.; BERGER,R.; LAUFER,G.; KOCHER,A.; ARTEMIOU,O.; BOLTZ-NITULESCU,G.; ROTH,E.
Clinical and Experimental Immunology 1999;115:315-323.
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Abstract
Changes in the differential blood cell count, monocyte phenotype and the cytokine plasma levels in a group of seven patients with cardiac surgery/cardiopulmonary bypass (CPB) and nine patients with thoracic surgery/without CPB, both receiving identical opioid-based anaesthetic technique, were assessed. A significant reduction in the number of circulating lymphocytes and monocytes was observed after anaesthesia and surgery. Interestingly, at the end of surgery as well as 1 day post-surgery a marked increase in the number of granulocytes was noted. General anaesthesia and surgery caused a significant reduction of HLA-DR and CD11c/CD18 molecules, starting immediately after induction of anaesthesia, and an increase of CD64 at day 1 after anaesthesia. The use of a CPB was followed by a significant reduction of CD32, CD16, CD54 and HLA-ABC antigens expression at the end of surgery. One day after surgery these parameters returned nearly to baseline values with the exception of CD54. A monocyte subpopulation, characterized by low CD14, high CD16 and HLA-DR expression (CD14+CD16+HLA-DR++) was found in both groups at each time point, and the percentage of this cell subset decreased from baseline to 24 h. The plasma concentrations of IL-6 and IL-10 increased considerably during CPB. No dynamic changes of IL-1 level due to surgery or CPB were found. We conclude that anaesthesia as well as the use of CPB induced profound alterations in the number of circulating leucocytes, and in the phenotype of monocyte and cytokine production
1506
Polarized secretion of Leukemia Inhibitory Factor
Hill,Eric J.; Vernallis,Ann B.
BMC Cell Biology 2008;9:53› Link
Abstract
The direction of cytokine secretion from polarized cells determines the cytokine's cellular targets. Leukemia inhibitory factor (LIF) belongs to the interleukin-6 (IL-6) family of cytokines and signals through LIFR/gp130. Three factors which may regulate the direction of LIF secretion were studied: the site of stimulation, signal peptides, and expression levels. Stimulation with IL-1¦ is known to promote IL-6 secretion from the stimulated membrane (apical or basolateral) in the human intestinal epithelial cell line Caco-2. Since LIF is related to IL-6, LIF secretion was also tested in Caco-2 following IL-1¦ stimulation. Signal peptides may influence the trafficking of LIF. Two isoforms of murine LIF, LIF-M and LIF-D, encode different signal peptides which have been associated with different locations of the mature protein in fibroblasts. To determine the effect of the signal peptides on LIF secretion, secretion levels were compared in Madin-Darby canine kidney (MDCK) clones which expressed murine LIF-M or LIF-D or human LIF under the control of an inducible promoter. Low and high levels of LIF expression were also compared since saturation of the apical or basolateral route would reveal specific transporters for LIF. Results When Caco-2 was grown on permeable supports, LIF was secreted constitutively with around 40% secreted into the apical chamber. Stimulation with IL-1¦ increased LIF production. After treating the apical surface with IL-1¦, the percentage secreted apically remained similar to the untreated, whereas, when the cells were stimulated at the basolateral surface only 20% was secreted apically. In MDCK cells, an endogenous LIF-like protein was detected entirely in the apical compartment. The two mLIF isoforms showed no difference in their secretion patterns in MDCK. Interestingly, about 70% of murine and human LIF was secreted apically from MDCK over a 400-fold range of expression levels within clones and a 200,000-fold range across clones. Conclusion The site of stimulation affected the polarity of LIF secretion, while, signal peptides and expression levels did not. Exogenous LIF is transported in MDCK without readily saturated steps
2649
Effect of intravenous pentoxifylline in inflammatory response in patients undergoing nephrolithotomy
Izadpanah,F.; Mojtahedzadeh,M.; Kazem Aghamir,S.M.; Atharikia,D.; Dashti,S.; Abbasi,A.
J Endourol. 2009;23:323-328.
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Abstract
PURPOSE: To determine the potential efficacy of intravenous (IV) infusion of pentoxifylline (PTX) before nephrolithotomy on attenuating plasma level of the tumor necrosis factor (TNF)-alpha and interleukin (IL)-1, and to investigate whether it prevents postoperative pain. PATIENTS AND METHODS: In a randomized, double-blind, placebo-controlled study, 32 patients (American Society of Anesthesiologists physical status 1 and 2) who were undergoing general anesthesia for nephrolithotomy were randomized to receive intravenous PTX (500 mg in 500 mL saline for 2 hours followed by 700 mg in 1000 mL saline for 6 hours), or placebo (1500 mL saline) before induction of the anesthesia. Two venous blood samples were obtained 10 minutes before PTX or placebo infusion and after surgery at 24 hours for laboratory examination. After surgery, the amount of narcotics consumption and intensity of pain (Visual Analog Scale and Verbal Rating Scale) were evaluated. RESULTS: At baseline, both placebo and PTX group had similar demographic, clinical, and laboratory characteristics. The use of narcotic analgesia (morphine, pethidine or both) was more common in the control group for pain relief. Also, pain intensity was significantly lower in patients who received PTX in comparison with those in the control group. Patients in the PTX group had lower postoperative plasma levels of TNF-alpha (0.27 pg/mL (0.06/0.74) v 3.35 pg/mL (0.83/6.41)) (median (25%/75%), P < 0.0001) and IL-6 (35.4 +/- 21.1 pg/mL (range 12-100) v 60.4 +/- 16.7 pg/mL (range 38-100), mean +/- standard deviation, P < 0.001) compared with the placebo receivers. There was no significant difference in surgery time, length of hospital stay, and fever occurrence after operation during in-hospital follow-up. Nausea and vomiting developed, however, in 5 (31.2%) of treatment patients. CONCLUSIONS: An infusion of IV PTX that is administered preoperatively could be applied to reduce inflammatory changes and pain intensity in patients undergoing nephrolithotomy; it causes no serious side effects
2727
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.
55
Serum hepcidin level and erythropoietic activity after hematopoietic stem cell transplantation
Kanda,Junya; Mizumoto,Chisaki; Kawabata,Hiroshi; Tsuchida,Hideyuki; Tomosugi,Naohisa; Matsuo,Keitaro; Uchiyama,Takashi
Haematologica 2008;93:1550-1554.
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Abstract
The relationship between serum hepcidin, a key regulator of body iron homeostasis, and erythropoiesis was investigated before and after stem cell transplantation in 31 patients with hematopoietic malignancies. Serum hepcidin-25 was monitored using a liquid chromatography-tandem mass spectrometry-based assay system. Other iron- and erythropoiesis-related parameters and known hepcidin regulators, such as interleukin-6 and growth differentiation factor-15, were also monitored. The serum hepcidin level peaked one week after stem cell transplantation, followed by a gradual decrease with a parallel change in interleukin-6 and a reciprocal change in reticulocyte count. Multivariate regression analysis demonstrated that the serum hepcidin level at four weeks after stem cell transplantation showed significant inverse correlations with erythropoietic activity markers, such as the soluble transferrin receptor, but not with growth differentiation factor-15. These results indicate the existence of an unknown functional erythropoiesis-associated circulating factor, other than growth differentiation factor-15, that negatively regulates hepcidin production in stem cell transplantation settings
2376
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
625
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
822
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.
994
Plasma leptin and insulin-like growth factor I levels during acute exacerbations of chronic obstructive pulmonary disease
Kythreotis,Prokopis; Kokkini,Ageliki; Avgeropoulou,Stavrina; Hadjioannou,Argyro; Anastasakou,Efgenia; Rasidakis,Antonis; Bakakos,Petros
BMC Pulmonary Medicine 2009;9:11› Link
Abstract
Recent studies have provided evidence for a link between leptin and tumor necrosis factor-alpha (TNF-¦). Insulin-like growth factor I (IGF-I) mediates the metabolic effects of growth hormone (GH). The GH axis is believed to be suppressed in chronic obstructive pulmonary disease (COPD). The aim of this study is to find out whether acute exacerbations of COPD are followed by changes in plasma leptin and insulin-like growth factor I (IGF-I) levels and furthermore, whether these changes are related to systemic inflammation. Methods We measured serum leptin, IGF-I, TNF-¦, interleukin 1¦ (IL-1¦), interleukin 6 (IL-6) and interleukin 8 (IL-8) levels in 52 COPD patients with acute exacerbation on admission to hospital (Day 1) and two weeks later (Day 15). 25 healthy age-matched subjects served as controls. COPD patients were also divided into two subgroups (29 with chronic bronchitis and 23 with emphysema). Serum leptin and IGF-I were measured by radioimmunoassay and TNF-¦, IL-1¦, IL-6 and IL-8 were measured by ELISA. Results Serum leptin levels were significantly higher and serum IGF-I levels significantly lower in COPD patients on Day 1 than in healthy controls (p < 0.001). A positive correlation was observed between leptin and TNF-¦ on Day 1 (r = 0.620, p < 0.001). Emphysematous patients had significantly lower IGF-I levels compared to those with chronic bronchitis both on Day 1 and Day 15 (p = 0.003 and p < 0.001 respectively). Conclusion Inappropriately increased circulating leptin levels along with decreased IGF-I levels occured during acute exacerbations of COPD. Compared to chronic bronchitis, patients with emphysema had lower circulating IGF-I levels both at the onset of the exacerbation and two weeks later
2665
Activation of podocytes by mesangial-derived TNF-{alpha}: glomerulo-podocytic communication in IgA nephropathy
Lai,Kar Neng; Leung,Joseph C.K.; Chan,Loretta Y.Y.; Saleem,Moin A.; Mathieson,Peter W.; Lai,Fernand M.; Tang,Sydney C.W.
Renal Physiology 2008;294:F945-F955.
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Abstract
We have previously documented that human mesangial cell (HMC)-derived TNF-{alpha} is an important mediator involved in the glomerulo-tubular communication in the development of interstitial damage in IgA nephropathy (IgAN). With the strategic position of podocytes, we further examined the role of mesangial cells in the activation of podocytes in IgAN. There was no binding of IgA from patients with IgAN to podocytes. Podocytes cultured with IgA from patients with IgAN did not induce the release of growth factors or cytokines. Furthermore, podocytes did not express mRNA of known IgA receptors. In contrast, IgA-conditioned medium (IgA-HMC medium) prepared by culturing HMC with IgA from patients with IgAN for 48 h significantly increased the gene expression and protein synthesis of TNF-{alpha} by podocytes with a 17-fold concentration above that of IgA-HMC medium. The upregulation of TNF-{alpha} expression by podocyte was only abolished by a neutralizing antibody against TNF-{alpha} but not by other antibodies. Exogenous TNF-{alpha} upregulated the synthesis of TNF-{alpha} by podocytes in an autocrine fashion. IgA-HMC medium prepared with IgA from patients with IgAN also significantly upregulated the expression of both TNF-{alpha} receptor 1 and 2 in podocytes. Our in vitro finding suggests podocytes may play a contributory role in the development of interstitial damage in IgAN by amplifying the activation of tubular epithelial cells with enhanced TNF-{alpha} synthesis after inflammatory changes of HMC
2444
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
Synthesis of TNF-{alpha} by mesangial cells cultured with polymeric anionic IgA role of MAPK and NF-{kappa}B
Leung,Joseph C.K.; Tang,Sydney C.W.; Chan,Loretta Y.Y.; Chan,Wai Long; Lai,Kar Neng
Nephrology Dialysis Transplantation 2008;23:72-81.
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Abstract
Background. Deposition of polymeric IgA1 (pIgA) in kidney mesangium is the hallmark of IgA nephropathy (IgAN). Current consensus is that a fraction of IgA1 molecules in the circulation of IgAN patients exhibit aberrant structures or properties that may lead to their deposition. Our previous findings suggest that the anionic property of IgA1 may play a role in mesangial IgA1 deposition in patients with IgAN. In the present study, the functional consequences of the binding of anionic polymeric IgA1 to human mesangial cells (HMCs) were investigated. Methods. Anionic polymeric IgA1 from IgAN patients and healthy subjects was isolated by sequential jacalin affinity chromatography, size exclusion chromatography using size exclusion and MonoQ ion exchange chromatography. HMCs were cultured with purified anionic polymeric IgA1 and the release of tumour necrosis factor-{alpha} (TNF-{alpha}) and interleukin-6 (IL-6) was examined by enzyme-linked immunosorbent assay. The signalling pathways involved in anionic pIgA-mediated HMC activation were examined by immunoblotting. Standard electrophoretic mobility shift assay (EMSA) was used to further examine whether the transcriptional factor NF-{kappa}B is associated in the signalling process. To define the mechanism of TNF-{alpha} and IL-6 production, HMCs were cultured with anionic pIgA in the presence or absence of p42/p44 mitogen-activated protein kinase (MAPK) inhibitor (PD98059), NF-{kappa}B inhibitor pyrrolidine dithiocarbamate (PDTC) or NF-{kappa}B blocking permeable peptides. Results. Compared with less anionic pIgA or monomeric IgA1 (mIgA), anionic pIgA from patient with IgAN significantly increased cell proliferation (P < 0.05) when cultured with HMC. These anionic pIgA significantly increased the synthesis of TNF-{alpha} (P < 0.05) and IL-6 (P < 0.05) in a dose and time-dependent manner. Furthermore, the increased synthesis of IL-6 and TNF-{alpha} by anionic pIgA in HMC was significantly diminished (P < 0.01) in the presence of NF-{kappa}B inhibitor pyrrolidine dithiocarbamate and NF-{kappa}B blocking permeable peptides SN50 (P < 0.01). The increased synthesis of IL-6 by anionic pIgA in HMC was reduced by inhibitor to NF-{kappa}B or p42/p44 MAPK and was abolished by the simultaneous presence of inhibitors to p42/p44 MAPK and NF-{kappa}B. The up-regulation of TNF-{alpha} was partially suppressed by inhibitor to NF-{kappa}B but not PD98059. Conclusion. Our results suggest that polymeric anionic IgA1 could activate HMC and increase the synthesis of TNF-{alpha} and IL-6. While both the p42/p44 MAPK and NF-{kappa}B pathways are essential in regulating the anionic pIgA-induced synthesis of IL-6, TNF-{alpha} synthesis mediated by anionic pIgA is partly dependent on NF-{kappa}B
2464
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
Prospective Randomized Comparison of Coronary Bypass Grafting With Minimal Extracorporeal Circulation System (MECC) Versus Off-Pump Coronary Surgery
Mazzei,Valerio; Nasso,Giuseppe; Salamone,Giovanni; Castorino,Filippo; Tommasini,Antonello; Anselmi,Amedeo
Circulation 2007;116:1761-1767.
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Abstract
Background-- We aimed to evaluate the clinical results and biocompatibility of the minimal extracorporeal circulation system (MECC) compared with off-pump coronary revascularization (OPCABG). Methods and Results-- In a prospective randomized study, 150 patients underwent coronary surgery with the use of MECC and 150 underwent OPCABG. End points were (1) circulating markers of inflammation and organ injury, (2) operative results, and (3) outcome at 1-year follow-up. Operative mortality and morbidity were comparable between the groups. Release of inflammatory markers was similar between groups at all time points (peak interleukin-6 167.2{+/-}13.5 versus 181{+/-}6.5 pg/mL, P=0.14, OPCABG versus MECC group, respectively). Peak creatine kinase was 419.3{+/-}103.5 versus 326{+/-}84.2 mg/dL (P=0.28), and peak S-100 protein was 0.13{+/-}0.08 versus 0.29{+/-}0.1 pg/mL (P=0.058, OPCABG versus MECC group, respectively). Length of hospital stay and use of blood products were similar between groups. Two cases of angina recurrence at 1 year in the MECC group were observed versus 5 cases observed in the OPCABG group (P=0.44). A residual perfusion defect at myocardial nuclear scan was less frequent among patients in the MECC group (3 versus 9 cases, P=0.14; odds ratio 0.32, 95% confidence interval 0.07 to 1.32). Six (OPCABG group) versus 3 (MECC group) coronary grafts were occluded or severely stenotic at 1 year (P=0.33, odds ratio 0.47, 95% confidence interval 0.09 to 2.14). Conclusions-- Clinical results of coronary revascularization with MECC are optimal when this procedure is performed by experienced teams. Postoperative morbidity is comparable to that with OPCABG. MECC is associated with little pump-related systemic and organ injury. It may achieve the benefits of OPCABG (less morbidity in high-risk patients) while facilitating complete revascularization in the case of complex lesions unsuitable for OPCABG
2484
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
Inflammatory Activation During Coronary Artery Surgery and Its Dose-Dependent Modulation by Statin/ACE-Inhibitor Combination
Radaelli,Alberto; Loardi,Claudia; Cazzaniga,Maria; Balestri,Giulia; DeCarlini,Caterina; Cerrito,M.Grazia; Cusa,Elena Negro; Guerra,Luca; Garducci,Stefano; Santo,Danilo; Menicanti,Lorenzo; Paolini,Giovanni; Azzellino,Arianna; Lavitrano,Maria Luisa; Mancia,Giuseppe; Ferrari,Alberto U.
Arteriosclerosis, Thrombosis, and Vascular Biology 2007;27:2750-2755.
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Abstract
Background-- On-pump coronary artery bypass graft (CABG) surgery triggers an inflammatory response (IR) which may impair revascularization. The study aimed at (1) characterizing the temporal profile of the IR by assaying appropriate markers in both systemic and coronary blood, and (2) determining whether (and which doses of) cardiovascular drugs known to have antiinflammatory properties, namely statins and ACE-inhibitors (ACEI), inhibit the response. Methods and Results-- Patients scheduled for CABG (n=22) were randomized to statin/ACEI combination treatment at standard doses (STD, ramipril 2.5/simvastatin 20 mg, or atorvastatin 10 mg), or at high doses (HiDo, ramipril 10 mg, or enalapril 20 mg/simvastatin 80 mg, or atorvastatin 40 mg). Plasma levels of interleukin 6, tumor necrosis factor alpha, E-selectin, von Willebrand factor (vWF), and sVCAM-1 were serially assayed (ELISA) before, during, and after CABG. Blood was drawn from an artery, a systemic vein, and the coronary sinus. Myocardial perfusion scans were obtained before and 2 months after surgery in 19 out of 22 subjects. In the STD group both IL-6 and TNF displayed striking increases which were similar at all sites and peaked 10 to 60 minutes after aortic declamping. Such increases were drastically attenuated in the HiDo group. Instead, only modest increases in venous E-selectin, vWF, and sVCAM-1 were observed. Scintigraphic ischemia scores were entirely normalized after versus before CABG in the HiDo but not in the STD treatment group. Conclusions-- On-pump CABG surgery is associated with an intense systemic inflammatory response, which can be almost completely prevented by early treatment with high (but not standard) doses of ACE-inhibitors and statins. CABG surgery triggers inflammation. Modulation of this response by statins/ACE-inhibitors (ACEI) was tested. Patients undergoing CABG were randomized to statin/ACEI treatment at standard (STD) or high doses (HiDo). Inflammatory mediators were assayed. Striking increases in inflammatory mediators were observed in the STD but not the HiDo group. CABG-related inflammatory response can be prevented by high doses of ACEI/statins
2473
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
Prevalence, Incidence, and Clinical Resolution of Insulin Resistance in Critically Ill Patients: An Observational Study
Saberi,Farzad; Heyland,Daren; Lam,Miu; Rapson,Dilys; Jeejeebhoy,Khursheed
Journal of Parenteral and Enteral Nutrition 2008;32:227-235.
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Abstract
Background: The primary objective of this study was to measure the prevalence, incidence, and resolution of insulin resistance (IR) in critically ill patients. A secondary objective was to explore the relationship between IR and inflammatory cytokines, coagulation abnormalities, and clinical outcomes. Design: Prospective observational study. Methods: The setting was the medical/surgical intensive care unit (ICU). We enrolled consecutive patients within 24 hours of admission to the ICU. Blood samples were collected daily until discharge, death, or a maximum of 10 days, then sent for measurement of markers of IR, inflammation, and coagulation. Charts were reviewed retrospectively to determine clinical outcomes. The homeostasis model assessment method (HOMA) was used to determine IR; a score of [≥] 4 represents insulin resistance. Results: A total of 96 patients were enrolled. Upon admission, 64 (67%) patients had overt IR (glucose > 7 mmol/L or insulin use), 9 (9.4%) had non-overt IR (normal glucose but HOMA > 4), and 23 (24%) were insulin sensitive (IS; normal glucose and HOMA < 4). During the course of ICU stay, an additional 16 patients developed overt IR, while 10 (10%) remained IS. There were no significant differences in inflammatory markers, coagulation tests, and clinical outcomes between IR and IS patients. There was no significant correlation between HOMA and inflammatory markers and coagulation markers. In a multivariable regression model, only interleukin-6 levels were significantly associated with mortality. Conclusions: A high proportion of critically ill patients have IR. There may not be any significant relationship between IR and measures of inflammation, coagulation, and clinical outcomes in a heterogeneous population of critically ill patients
2514
Down-regulation of adhesion molecules and other inflammatory biomarkers after moderate wine consumption in healthy women: a randomized trial
Sacanella,Emilio; Vazquez-Agell,Monica; Mena,Mari Pau; Antunez,Emilia; Fernandez-Sola,Joaquim; Nicolas,Jose Maria; Lamuela-Raventos,Rosa M.; Ros,Emilio; Estruch,Ramon
American Journal of Clinical Nutrition 2007;86:1463-1469.
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Abstract
Background: Moderate alcohol consumption is cardioprotective. The mechanism for this beneficial effect might be reduced inflammatory responses, as suggested by prospective studies and small clinical trials in men. No studies have evaluated the antiinflammatory effects of wine in women. Objective: We investigated whether low-dose intake of white and red wines has differential effects on inflammatory markers in women. Design: In a crossover study, we randomly assigned 35 healthy women to two 4-wk periods of 20 g ethanol/d as white or red wine, preceded by two 4-wk washout periods. Before and after interventions, we measured serum lipids, circulating inflammatory biomarkers, cellular adhesion molecules (CAMs), and adhesion of monocytes to stimulated endothelial cells. Results: HDL cholesterol increased, and the serum concentrations of high-sensitivity C-reactive protein, intercellular adhesion molecule-1, CD40L, and interleukin-6 decreased after either wine (P < 0.01, all). Vascular CAM-1 and E-selectin decreased (P < 0.01) only after red wine. CAM expression by mononuclear cells was blunted after either wine, with a greater suppressant effect of red wine. Enhanced adhesion of monocytes to stimulated endothelial cells was reduced by 51% (95% CI: -57%, -45%) after white wine and by 89% (95% CI: -96%, -82%) after red wine (P = 0.01 for between-wine differences). Conclusions: Moderate wine consumption is associated with beneficial effects on various inflammatory pathways related to endothelial activation in women. Probably because of its higher polyphenol content, red wine shows superior antiinflammatory effects than does white wine. Reducing low-grade inflammation and endothelial activation may be another potential mechanism by which alcoholic beverages exert their cardioprotective effect
2305
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
Schröder,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
In Vivo and In Vitro Glucocorticoid Sensitivity in Obese People With Cushingoid Appearance
Syed,Akheel; Redfern,Christopher P.F.; Weaver,Jolanta
Obesity 2008;16:2374-2378.
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Abstract
Clinical similarities between Cushing's syndrome and obesity/metabolic syndrome have led to speculation of a role for glucocorticoids (GCs) in the etiopathogenesis of obesity. People with idiopathic obesity have normal circulating cortisol concentrations. However, there may be considerable interindividual variation in GC sensitivity. The objective of this study was to determine whether enhanced GC sensitivity in the absence of GC excess was a characteristic of obese people with cushingoid features. We studied 12 obese subjects with cushingoid features in the absence of Cushing's syndrome and six slim control participants. Data recorded included BMI, waist-to-hip ratio, blood pressure, glucose and insulin response to 75 g oral glucose challenge, and low-dose (0.25 mg) overnight dexamethasone (DEX) suppression test (ODST-0.25 mg). To study GC-sensitivity in vitro, we performed dose-response studies of DEX-induced suppression of interleukin-6 (IL-6) secretion in skin fibroblast cultures. Seven obese subjects were normosensitive and five subjects hypersensitive to GCs in vitro. ODST-0.25 mg resulted in a median suppression of cortisol from baseline of 32% in normosensitive and 60% in hypersensitive obese subjects (P < 0.004). No other clinical or biochemical measures were discriminatory between these two groups. These data from two independent measures of GC sensitivity suggest that enhanced GC sensitivity may characterize a substantial proportion of obese people with cushingoid appearance.
2275
Heat Shock Proteins 27, 60, 70, 90{alpha}, and 20S Proteasome in On-Pump Versus Off-Pump Coronary Artery Bypass Graft Patients
Szerafin,Tamas; Hoetzenecker,Konrad; Hacker,Stefan; Horvath,Ambrus; Pollreisz,Andreas; Arpad,Peterffy; Mangold,Andreas; Wliszczak,Tina; Dworschak,Martin; Seitelberger,Rainald; Wolner,Ernst; Ankersmit,Hendrik J.
Annals of Thoracic Surgery 2008;85:80-87.
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Abstract
BackgroundThe secretion of heat shock protein (HSP) 27, HSP60, HSP70, HSP90{alpha}, 20S proteasome, and their correlations to proinflammatory cytokine interleukin-6 is unknown in patients undergoing on-pump versus off-pump coronary artery bypass graft (CABG) operation. MethodsForty patients were included in this explorative study (on- versus off-pump CABG, each n = 20). Serum samples were obtained before and 30 minutes, 60 minutes, and 24 hours after CABG operation. Enzyme-linked immunosorbent assay technique was utilized to determine soluble HSP27, 60, 70, and 90{alpha}, 20S proteasome, and levels of interleukin-6. ResultsSerum levels of HSP are increased in patients undergoing on-pump CABG operation as compared with off-pump CABG technique. These differences were highly significant for HSP27, 70, and 90{alpha} at 60 minutes after initiation of cardiopulmonary bypass (all, p < 0.001). Concentrations of soluble 20S proteasome were increased 24 hours after operation in on- and off-pump CABG patients (p < 0.001) and correlated significantly with the serum content of HSP 27, 70, and 90{alpha} at 60 minutes after initiation of cardiopulmonary bypass (p < 0.001). No correlation was found when comparing interleukin-6 levels with intravascular leakage of HSP and 20S proteasome after CABG operation. ConclusionsWe conclude from our data that the innate immune system is activated owing to spillage of known immune modulatory and apoptosis-associated proteins after CABG operation
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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
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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).
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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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Protective effect of peroxisome proliferator-activated receptor-gamma agonists on activated renal proximal tubular epithelial cells in IgA nephropathy
Xiao,Jing; Leung,Joseph C.K.; Chan,Loretta Y.Y.; Guo,Hong; Lai,Kar Neng
Nephrology Dialysis Transplantation 2009;› Link
Abstract
Background. We have previously demonstrated a glomerulo-tubular crosstalk' operating in the pathogenesis of tubulointerstitial injury in IgA nephropathy (IgAN). The present study aims to explore any possible beneficial effect of a peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) agonist in alleviating the tubulointerstitial inflammation in IgAN. Methods. Human proximal tubular epithelial cells (PTEC) were pre-treated with increasing concentration of a PPAR-{gamma} agonist rosiglitazone or troglitazone (0-5 {micro}M) followed by further incubation with the conditioned medium (IgA-HMC) collected from human mesangial cells (HMC) incubated with polymeric IgA isolated from IgAN patients. Gene expression of interleukin-6 (IL-6) and angiotensin II type 1 receptor (ATR1) was detected by reverse transcription-polymerase chain reaction (RT-PCR); protein expression of IL-6 and ATR1 was determined by ELISA and western blot, respectively. The mitogen-activated protein kinase extracellular signal-related kinase 1/2 (ERK1/2) activation was examined by western blot. Results. An IgA-HMC conditioned medium prepared from IgAN patients increased gene expression and protein synthesis of IL-6 and ATR1 in PTEC when compared with a conditioned medium prepared from healthy controls. The upregulated gene expression and protein synthesis of IL-6 and ATR1 in PTEC induced by the IgA-HMC conditioned medium were readily attenuated following pre-treatment with a PPAR-{gamma} agonist, thiazolidinedione (TZD). The ATR1-downregulating effect exerted by the PPAR-{gamma} agonist occurred through the inhibition of ERK1/2 activation. The PPAR-{gamma} antagonist, GW9662, significantly attenuated the inhibitory action of rosiglitazone on the increased synthesis of IL-6 and ATR1 protein. Conclusion. Our current findings suggest that the PPAR-{gamma} agonist attenuates excessive inflammatory response in activated PTEC in IgAN through suppressing ATR1 expression. This ATR1-downregulating effect is likely through the inhibition of ERK1/2 activation and is found to be PPAR-{gamma} dependent. TZDs may possibly be new therapeutic additives to established treatment regime for renin-angiotensin system (RAS) blockade in IgAN
2404
Evaluation of beneficial and adverse effects of glucocorticoids on a newly developed full-thickness skin model
Zöller,Nadja Nicole; Kippenberger,Stefan; Thaçi,Diamant; Mewes,Karsten; Spiegel,Martina; Sättler,Andrea; Schultz,Maike; Bereiter-Hahn,Jürgen; Kaufmann,Roland; Bernd,August
Toxicology in Vitro 2008;22:747-759.
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Abstract
Glucocorticoids (GCs) are highly effective compounds widely used in the treatment of inflammatory diseases; however, they offer distinct adverse effects such as skin thinning in response to long-term topical treatment. Nevertheless it is difficult to deduce the safety of a newly synthesized compound from its structural formula. Efficient assay systems that measure beneficial and adverse effects are needed. In the present study the applicability of a three-dimensional full-thickness skin model (FTSM) is tested to display GC-induced effects regarding anti-inflammation and atrophy. It is shown that topical application of a commercial GC ointment suppresses the ultraviolet (UV)B induced induction of interleukin (IL)-6 and IL-8. Addition of purified betamethasone-17-valerate, prednicarbate and clobetasol-17-propionate to the culture medium for 14 days caused a reduction in the number of epidermal cell-layers corresponding to the atrophic risk found in vivo. Similarly, repeated topical application of five GC creams induced epidermal thinning. Evidence is given that the inhibitory effect on keratinocyte proliferation contributes to this effect. Furthermore, dermal thinning was monitored by measuring type I collagen synthesis; a decreased collagen synthesis similar to the in vivo situation is shown. The present study demonstrates the versatility of this FTSM in the validation of effectiveness and safety of GCs.
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