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Objective: Hyperthyroidism increases cardiovascular morbidity and mortality, but the underlying mechanisms are not fully understood. In this study, we compared non-invasive haemodynamics between 20 hyperthyroid patients and 60 euthyroid subjects. Methods: The measurements were performed median 6 days after the initiation of antithyroid medication when the patients were still hyperthyroid. Three controls matched for age, sex, body mass index, and smoking status were selected for each patient. Recordings were performed during rest and passive head-up tilt using whole-body impedance cardiography, radial pulse wave analysis, and finger blood pressure measurements. Results: Systolic and diastolic blood pressures in the aorta and radial artery were similar in hyperthyroid and euthyroid subjects, while finger blood pressure was 16/12 mm Hg lower in hyperthyroidism (P < 0.001). Pulse wave velocity and aortic pulse pressure were similar, but radial pulse pressure was ~5 mm Hg higher in hyperthyroidism (P = 0.040) due to augmented amplification (P = 0.045). Systemic vascular resistance was reduced (−18%), whereas heart rate (+19 beats/min), cardiac index (+28%), and left cardiac work (+31%) were increased in hyperthyroidism (P < 0.001). Subendocardial viability ratio, reflecting the balance between coronary perfusion and pressure load, was reduced by 19% in hyperthyroidism (P < 0.001). Compared with euthyroid subjects, hyperthyroid patients presented with reductions in systolic and diastolic finger blood pressures (P < 0.001), and a higher increase in heart rate (P = 0.014) during upright posture. Conclusions: Hyperthyroid patients exhibited hyperdynamic circulation, reduced vascular resistance, reduced peripheral but not central blood pressure, and higher pulse pressure amplification. Furthermore, the left cardiac workload was increased in parallel with unfavourable changes in coronary perfusion conditions.

Abstract Background Angiogenesis is crucial for tumor development, progression, and metastasizing. The most important regulator of angiogenesis is the vascular endothelial growth factor (VEGF) family, which is involved in multiple pathways in tumor microenvironment. The objective of this study was to investigate the prognostic value of the VEGF family in patients treated for metastatic breast cancer. The emphasis was on neuropilin-1 (NRP-1) and placental growth factor (PlGF). Materials and methods An analysis of eight members of the VEGF family was performed using baseline plasma samples of 65 patients treated for metastatic HER2 negative breast cancer in a phase II first-line bevacizumab plus chemotherapy trial. The patients were divided into two groups, high or low, according to the median for each VEGF family member. Progression-free survival (PFS) and overall survival (OS) were determined for each VEGF family member. Results The patients with low plasma levels of NRP-1 and PlGF had a longer OS than those with high plasma levels [multivariable adjusted hazard ratios (HRs) 2.54 (95% confidence interval (CI) 1.11–5.82, p = 0.02) and 3.11 (95% CI 1.30–7.47, p = 0.01), respectively]. The patients with low levels of both NRP-1 and PlGF had a remarkably long OS with HR of 6.24, (95% CI 1.97–19.76, p = 0.002). In addition, high baseline NRP-1 level was associated with a significantly shorter PFS [multivariable adjusted HR 2.90 (95% CI 1.02–8.28, p = 0.04)] than that in the low-level group, and a high baseline vascular endothelial growth factor receptor-2 level was associated with a longer PFS [multivariable adjusted HR 0.43 (95% CI 0.19–0.98, p = 0.04)]. Conclusion Especially NRP-1 and PlGF have prognostic potential in metastatic breast cancer patients treated with a bevacizumab-taxane combination. Patients with low plasma levels of NRP-1 or PlGF have longer OS than patients with high levels. Patients with both low NRP-1 and PlGF levels appear to have excellent long-term survival. Trial registration ClinicalTrials.gov identifier: NCT00979641, registration date 18/09/2009. The regional Ethics Committee: R08142M, registration date 18/11/2008.

Purpose High sodium intake is an accepted risk factor for hypertension, while low Na+ intake has also been associated with increased risk of cardiovascular events. In this cross-sectional study, we examined the association of 24-h urinary Na+ excretion with haemodynamics and volume status. Materials and methods Haemodynamics were recorded in 510 normotensive and never-treated hypertensive subjects using whole-body impedance cardiography and tonometric radial artery pulse wave analysis. The results were examined in sex-specific tertiles of 24-h Na+ excretion, and comparisons between normotensive and hypertensive participants were also performed. Regression analysis was used to investigate factors associated with volume status. The findings were additionally compared to 28 patients with primary aldosteronism. Results The mean values of 24-h urinary Na+ excretion in tertiles of the 510 participants were 94, 148 and 218 mmol, respectively. Average tertile age (43.4–44.7 years), office blood pressure and pulse wave velocity were corresponding in the tertiles. Plasma electrolytes, lipids, vitamin D metabolites, parathyroid hormone, renin activity, aldosterone, creatinine and insulin sensitivity did not differ in the tertiles. In supine laboratory recordings, there were no differences in aortic systolic and diastolic blood pressure, heart rate, cardiac output and systemic vascular resistance. Extracellular water volume was higher in the highest versus lowest tertile of Na+ excretion. In regression analysis, body surface area and 24-h Na+ excretion were independent explanatory variables for extracellular water volume. No differences in urine Na+ excretion and extracellular water volume were found between normotensive and hypertensive participants. When compared with the 510 participants, patients with primary aldosteronism had 6.0% excess in extracellular water (p = .003), and 24-h Na+ excretion was not related with extracellular water volume. Conclusion In the absence of mineralocorticoid excess, Na+ intake, as evaluated from 24-h Na+ excretion, predominantly influences extracellular water volume without a clear effect on blood pressure.

Abstract Background Obesity-related hypertension and the associated metabolic abnormalities are considered as a distinct hypertensive phenotype. Here we examined how abdominal fat content, as judged by waist:height ratio, influenced blood pressure and hemodynamic profile in normotensive subjects and never-treated hypertensive patients. Methods The 541 participants (20–72 years) underwent physical examination and laboratory analyses and were divided into age and sex-adjusted quartiles of waist:height ratio. Supine hemodynamics were recorded using whole-body impedance cardiography, combined with analyses of radial tonometric pulse wave form and heart rate variability. Results Mean waist:height ratios in the quartiles were 0.46, 0.51, 0.55 and 0.62. Radial and aortic blood pressure, systemic vascular resistance, pulse wave velocity, markers of glucose and lipid metabolism, leptin levels and C-reactive protein were higher in quartile 4 when compared with quartiles 1 and 2 (p

Abstract Background Systemic sclerosis is a rheumatoid disease best known for its fibrotic skin manifestations called scleroderma. Alternatively activated (M2-type) macrophages are normally involved in the resolution of inflammation and wound healing but also in fibrosing diseases such as scleroderma. TRPA1 is a non-selective cation channel, activation of which causes pain and neurogenic inflammation. In the present study, we investigated the role of TRPA1 in bleomycin-induced skin fibrosis mimicking scleroderma. Methods Wild type and TRPA1-deficient mice were challenged with intradermal bleomycin injections to induce a scleroderma-mimicking disease. Macrophages were investigated in vitro to evaluate the underlying mechanisms. Results Bleomycin induced dermal thickening and collagen accumulation in wild type mice and that was significantly attenuated in TRPA1-deficient animals. Accordingly, the expression of collagens 1A1, 1A2, and 3A1 as well as pro-fibrotic factors TGF-beta, CTGF, fibronectin-1 and YKL-40, and M2 macrophage markers Arg1 and MRC1 were lower in TRPA1-deficient than wild type mice. Furthermore, bleomycin was discovered to significantly enhance M2-marker expression particularly in the presence of IL-4 in wild type macrophages in vitro, but not in macrophages harvested from TRPA1-deficient mice. IL-4-induced PPARγ-expression in macrophages was increased by bleomycin, providing a possible mechanism behind the phenomenon. Conclusions In conclusion, the results indicate that interfering TRPA1 attenuates fibrotic and inflammatory responses in bleomycin-induced scleroderma. Therefore, TRPA1-blocking treatment could potentially alleviate M2 macrophage driven diseases like systemic sclerosis and scleroderma.

Abstract Background The role of Interleukin-1 Receptor antagonist (IL-1Ra), an innate antagonist to pro-inflammatory cytokine IL-1, has attracted increasing attention due to its potential pathogenic and therapeutic implications in depression. However, the role of alcohol and adiposity in modulating IL-1Ra cytokine pathway in depressed patients has remainned unknown. The aim of this study was to follow the changes in IL-1Ra serum levels in depressed patients with or without simultaneous alcohol use disorder (AUD) and different degrees of adiposity during 6 months of follow-up. Materials and methods A total of 242 patients with depression were followed for 6 months. At baseline 99 patients had simultaneous AUD. Levels of serum IL-1Ra and common mediators of inflammation (IL-6, hs-CRP) were measured. Clinical assessments included Body Mass Index (BMI), Montgomery-Asberg Depression Rating Scale (MADRS) and Alcohol Use Disorders Identification Test (AUDIT) scores. Results Significant reductions in clinical symptoms and IL-1Ra were observed during 6-month follow-up. In hierarchical linear regression analysis, the effect of MADRS score, age, gender, and smoking had a combined effect of 2.4% in the model. The effect of AUDIT score increased the effect to 4.2% of variance (p = 0.08), whereas adding BMI increased the effect to 18.5% (p

Objective Acute volume overload (AVO) induces early ischemia-like changes in intramyocardial arteries. We investigated whether the Factor Xa (FXa) inhibitor apixaban interacts with the myocardium early after AVO. Methods Fifty-five syngeneic Fisher rats underwent surgical abdominal aortocaval fistula to induce AVO. Among them, 17 rats were treated with apixaban (10 mg/kg/day). The myocardial outcome was studied using histological analysis and by measuring atrial natriuretic peptide (ANP) and matrix metalloprotease 9 (MMP9) gene expression. Results After 3 days, the total number of intramyocardial arteries was significantly increased in the AVO +apixaban (AVO+A) group compared with that in the AVO group (12.0 ± 1.2 and 10.2 ± 1.5, point score units, respectively). In the AVO+A group, there were significantly more edematous nuclei in myocardial arteries in the right and left ventricle compared with that in the AVO group. ANP and MMP9 expression levels continued to increase significantly in the AVO+A group compared with those in the AVO group. Conclusion Apixaban interacts with intramyocardial arteries in the left and right ventricles after AVO and ANP and MMP9 expression levels increased. Thus, the myocardial effect of Factor Xa inhibition needs to be monitored after AVO.

Abstract Background Intra-articular glucocorticoid (GC) injections are widely used as a symptomatic treatment for osteoarthritis (OA). However, there are also concerns about their potentially harmful effects, and their detailed effects on chondrocyte phenotype remain poorly understood. Methods We studied the effects of dexamethasone on gene expression in OA chondrocytes with RNA-Seq. Chondrocytes were isolated from the cartilage from OA patients undergoing knee replacement surgery and cultured with or without dexamethasone for 24 h. Total RNA was isolated and sequenced, and functional analysis was performed against the Gene Ontology (GO) database. Results for selected genes were confirmed with RT-PCR. We also investigated genes linked to OA in recent genome-wide expression analysis (GWEA) studies. Results Dexamethasone increased the expression of 480 and reduced that of 755 genes with a fold change (FC) 2.0 or greater. Several genes associated with inflammation and cartilage anabolism/catabolism as well as lipid and carbohydrate metabolism were among the most strongly affected genes. In the GO analysis, genes involved in the extracellular matrix organization, cell proliferation and adhesion, inflammation, and collagen synthesis were enriched among the significantly affected genes. In network analysis, NGF, PI3KR1, and VCAM1 were identified as central genes among those most strongly affected by dexamethasone. Conclusions This is the first study investigating the genome-wide effects of GCs on the gene expression in OA chondrocytes. In addition to clear anti-inflammatory and anticatabolic effects, GCs affect lipid and glucose metabolism in chondrocytes, an observation that might be particularly important in the metabolic phenotype of OA.

Objectives: To search for biomarkers of RT-induced cardiotoxicity, we studied the behavior of ST2 during RT and three years after RT, and the associations with echocardiographic changes. Materials and methods: We measured soluble ST2 (ng/ml) in serum samples from 63 patients receiving RT for early breast cancer. Sampling and echocardiography were performed at baseline, after RT and at the three-year follow-up. Patients were grouped by >15% (group 1) and ≤15% (group 2) relative worsening in global longitudinal strain (GLS). Results: ST2 levels tended to increase during RT, from a median (interquartile range; IQR) of 17.9 (12.4–22.4) at baseline to 18.2 (14.1–23.5) after RT (p = 0.075). By the three-year follow up, ST2 levels increased to 18.7 (15.8–24.2), p = 0.018. The increase in ST2 level was associated with worsening cardiac systolic function at three-year follow-up, GLS (rho = 0.272, p = 0.034) and left ventricular ejection fraction (LVEF) (rho = ─0.343, p = 0.006). Group 1 (n = 14) had a significant increase in ST2 levels from 17.8 (12.3–22.5) at baseline to 18.4 (15.6–22.6) after RT, p = 0.035 and to 19.9 (16.0–25.1) three years after RT, p = 0.005. ST2 levels were stable in group 2 (n = 47): 17.8 (12.3–22.0) at baseline, 17.7 (12.6–23.5) after RT and 18.0 (15.5–22.4) at three years. Conclusion: ST2 may be useful for determining which patients are at risk for long-term cardiovascular toxicity following adjuvant breast cancer RT, but prospective clinical studies are needed to confirm this hypothesis.

Macrophages are pleiotropic immune cells whose phenotype can polarize towards the pro-inflammatory M1 or anti-inflammatory M2 direction as a response to environmental changes. In obesity, the number of macrophages in adipose tissue is enhanced, and they shift towards the M1 phenotype. Activated M1 macrophages secrete pro-inflammatory cytokines and adipokines involved in the development of systemic low-grade inflammation, complicating obesity. Polyphenols are widely found in the vegetable kingdom and have anti-inflammatory properties. We and others have recently found that lingonberry (Vaccinium vitis-idaea L.) supplementation is able to prevent the development of low-grade inflammation and its metabolic consequences in experimentally induced obesity. In the present study, we investigated the effects of twelve phenolic compounds known to be present in lingonberry (resveratrol, piceid, quercetin, kaempferol, proanthocyanidins, delphinidin, cyanidin, benzoic acid, cinnamic acid, coumaric acid, caffeic acid, and ferulic acid) on macrophage polarization, which is a meaningful mechanism determining the low-grade inflammation in obesity. Mouse J774 and human U937 macrophages and commercially available phenolic compounds were used in the studies. Three of the twelve compounds investigated showed an effect on macrophage polarization. Resveratrol, kaempferol, and proanthocyanidins enhanced anti-inflammatory M2-type activation, evidenced as increased expression of Arg-1 and MRC-1 in murine macrophages and CCL-17 and MRC-1 in human macrophages. Resveratrol and kaempferol also inhibited pro-inflammatory M1-type activation, shown as decreased expression of IL-6, NO, and MCP-1 in murine macrophages and TNF-α and IL-6 in human macrophages. In the further mechanistic studies, the effects of the three active compounds were investigated on two transcription factors important in M2 activation, namely on PPARγ and STAT6. Resveratrol and kaempferol were found to enhance PPARγ expression, while proanthocyanidins increased the phosphorylation of STAT6. The results suggest proanthocyanidins, resveratrol, and kaempferol as active constituents that may be responsible for the positive anti-inflammatory effects of lingonberry supplementation in obesity models. These data also extend the previous knowledge on the anti-inflammatory effects of lingonberry and encourage further studies to support the use of lingonberry and lingonberry-based products as a part of a healthy diet.

The aim of the present study was to investigate the levels of YKL-40 during and after coronary artery bypass grafting surgery (CABG) and to establish possible connections between YKL-40 and markers of oxidative stress, inflammation, and myocardial injury. Patients undergoing elective CABG utilizing cardiopulmonary bypass (CPB) were recruited into the study. Blood samples were collected at the onset of anesthesia, during surgery and post-operatively. Levels of YKL-40, 8-isoprostane, interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1) and troponin T (TnT) were measured by immunoassay. YKL-40 levels increased significantly 24 h after CPB. Positive correlation was seen between post-operative TnT and YKL-40 levels (r = 0.457, p = 0.016) and, interestingly, baseline YKL-40 predicted post-operative TnT increase (r = 0.374, p = 0.050). There was also a clear association between YKL-40 and the chemotactic factors MCP-1 (r = 0.440, p = 0.028) and IL-8 (r = 0.484, p = 0.011) linking YKL-40 to cardiac inflammation and fibrosis following CABG. The present results show, for the first time, that YKL-40 is associated with myocardial injury and leukocyte-activating factors following coronary artery bypass surgery. YKL-40 may be a factor and/or biomarker of myocardial inflammation and injury and subsequent fibrosis following heart surgery.

Abstract Objectives Vascular endothelial growth factor (VEGF) has been related to the etiology of major depressive disorder (MDD). The findings involving the effects of electroconvulsive therapy (ECT) on the VEGF levels have been conflicting. The aim was to examine the possible changes in the VEGF levels and their associations with clinical outcome in patients with MDD during ECT. Methods The study comprised 30 patients suffering from MDD. Their plasma VEGF levels were measured at baseline and 2 and 4 hr after the first, fifth, and last ECT session. The severity of depression was quantified by the Montgomery‐Asberg Depression Rating Scale (MADRS). Results The VEGF levels increased between the 2‐hr and 4‐hr measurements during the first (p = .003) and the fifth (p = .017) sessions. The baseline VEGF levels between individual ECT sessions remained unchanged during the ECT series. No correlations were found between the increased VEGF levels and the clinical outcome. Conclusions Electroconvulsive therapy increased the VEGF levels repeatedly at the same time point in two different ECT sessions. These increases had no association with the response to ECT. Consequently, VEGF may act as a mediator in the mechanism of action of ECT.

Abstract Background Transforming growth factor beta 1 (TGF-β1) and platelet-derived growth factor (PDGF) are cytokines involved in fibrotic processes causing radiotherapy (RT)-induced cardiovascular changes. We aimed to investigate the associations between TGF-β1 and PDGF and the echocardiographic changes that occur during RT and during three-year follow-up. Methods The study included 63 women receiving adjuvant RT for early-stage breast cancer or ductal carcinoma in situ. Serum TGF-β1 (ng/ml) and PDGF (ng/ml) levels were measured by enzyme-linked immunoassay and echocardiographic examination was performed before RT, after RT and at 3 years. Patients were grouped by biomarker behavior by a trajectory analysis. Results TGF-β1 decreased from 19.2 (IQR 17.1–22.3) before RT to 18.8 (14.5–22.0) after RT (p = 0.003) and the decrease persisted at 17.2 (13.7–21.2) 3 years after RT (p = 0.101). PDGF decreased from 15.4 (12.6–19.1) before RT to 13.8 (11.7–16.2) after RT, p = 0.001, and persisted at 15.6 (10.4–18.4) at 3 years, p = 0.661. The TGF-β1 level before RT (Spearman’s rho 0.441, p

Abstract Background Angiopoietin growth factors (Angs) regulate angiogenesis and lymphangiogenesis by binding to the endothelial Tie2 receptor. Ang2 expression is elevated in tissue hypoxia and inflammation, which also induce cleavage of the extracellular domain of the orphan Tie1 receptor. Here we have examined if the concentrations of Ang2 and the soluble extracellular domain of Tie1 in patient plasma are associated with the prognosis of patients with metastatic breast cancer. Methods Plasma Tie1 and Ang2 levels were measured in metastatic breast cancer patients treated in a phase II trial with a taxane-bevacizumab combination chemotherapy in the first-line treatment setting. They were analyzed before treatment, after 6 weeks and 6 months of treatment, and at the final study visit. Using the median concentrations as cutoffs, Tie1 and Ang2 data were dichotomized into low and high concentration groups. Additionally, we analyzed Tie1 concentrations in plasma from 10 healthy women participating in a breast cancer primary prevention study. Results Plasma samples were available from 58 (89%) of the 65 patients treated in the trial. The baseline Tie1 levels of the healthy controls were significantly lower than those of the metastatic patients (p

Obesity is a constantly increasing health problem worldwide. It is associated with a systemic low-grade inflammation, which contributes to the development of metabolic disorders and comorbidities such as type 2 diabetes. Diet has an important role in the prevention of obesity and its adverse health effects; as a part of healthy diet, polyphenol-rich berries, such as lingonberry (Vaccinium vitis-idaea L.) have been proposed to have health-promoting effects. In the present study, we investigated the effects of lingonberry supplementation on high-fat diet induced metabolic and inflammatory changes in a mouse model of obesity. Thirty male C57BL/6N mice were divided into three groups (n = 10/group) to receive low-fat (LF), high-fat (HF) and lingonberry-supplemented high-fat (HF+LGB) diet for six weeks. Low-fat and high-fat diet contained 10% and 46% of energy from fat, respectively. Lingonberry supplementation prevented the high-fat diet induced adverse changes in blood cholesterol and glucose levels and had a moderate effect on the weight and visceral fat gain, which were 26% and 25% lower, respectively, in the lingonberry group than in the high-fat diet control group. Interestingly, lingonberry supplementation also restrained the high-fat diet induced increases in the circulating levels of the proinflammatory adipocytokine leptin (by 36%) and the inflammatory acute phase reactant serum amyloid A (SAA; by 85%). Similar beneficial effects were discovered in the hepatic expression of the inflammatory factors CXCL-14, S100A10 and SAA by lingonberry supplementation. In conclusion, the present results indicate that lingonberry supplementation significantly prevents high-fat diet induced metabolic and inflammatory changes in a murine model of obesity. The results encourage evaluation of lingonberries as a part of healthy diet against obesity and its comorbidities.

Abstract Background Radiation-induced heart disease is mainly caused by activation of the fibrotic process. Transforming growth factor-beta 1 (TGF-β1) and platelet-derived growth factor (PDGF) are pro-fibrotic mediators. The aim of our study was to evaluate the behavior of TGF-β1 and PDGF during adjuvant radiotherapy (RT) for breast cancer and the association of these cytokines with echocardiographic changes. Methods Our study included 73 women with early-stage breast cancer or ductal carcinoma in situ (DCIS) receiving post-operative RT but not chemotherapy. TGF-β1 and PDGF levels in serum samples taken before and on the last day of RT were measured by an enzyme-linked immunosorbent assay. Echocardiography was also performed at same time points. Patients were grouped according to a ≥ 15% worsening in tricuspid annular plane systolic excursion (TAPSE) and pericardium calibrated integrated backscatter (cIBS). Results In all patients, the median TGF-β1 decreased from 25.0 (IQR 21.1–30.3) ng/ml to 23.6 (IQR 19.6–26.8) ng/ml (p = 0.003), and the median PDGF decreased from 18.0 (IQR 13.7–22.7) ng/ml to 15.6 (IQR 12.7–19.5) ng/ml (p

Objective: Patients with aneurysmal subarachnoid hemorrhage (aSAH) experience high mortality and morbidity. Neuroinflammation causes brain damage expansion after aSAH. Due to the complexity of the inflammatory response multiple biomarkers are needed to evaluate its' progression. We studied inflammatory process after aSAH by measuring two inflammatory biomarkers, interleukin-6 (IL-6) and high-mobility group box 1 (HMGB1) at simultaneous time-points after aSAH. Methods: In this prospective population-based study, IL-6 and HMGB1 were measured in aSAH patients (n = 47) for up to five days. Plasma concentrations of IL-6 and HMGB1 were measured at 0, 12 and 24 h after hospital admission, and thereafter daily for up to five days or until the patient was transferred from the intensive care unit (ICU). The patients' neurological outcomes were evaluated with the modified Rankin Scale at six months after aSAH. Results: A high IL-6 level during the first day after aSAH was associated with a severe initial clinical presentation (p = 0.002) and infection during follow-up (p = 0.031). The HMGB1 level did not associate with these parameters. There was no correlation between IL-6 and HMGB1 levels at any time point during the follow-up. The concentrations of IL-6 and HMGB1 were not associated with neurological outcome. Conclusions: High initial IL-6 values seem to reflect the intensity of the inflammatory response but not the brain damage per se. An early inflammatory response might even be beneficial since although elevated IL-6 levels were observed in patients with a more severe initial clinical presentation, they were not associated with neurological outcome. The lack of correlation between IL-6 and HMGB1 questions the role of macrophages in the process of the secretion of these inflammatory markers after aSAH, instead pointing to the activation of alternative pro-inflammatory pathways.

Pinosylvin is a natural stilbenoid found particularly in Scots pine. Stilbenoids are a group of phenolic compounds identified as protective agents against pathogens for many plants. Stilbenoids also possess health-promoting properties in humans; for instance, they are anti-inflammatory through their suppressing action on proinflammatory M1-type macrophage activation. Macrophages respond to environmental changes by polarizing towards proinflammatory M1 phenotype in infection and inflammatory diseases, or towards anti-inflammatory M2 phenotype, mediating resolution of inflammation and repair. In the present study, we investigated the effects of pinosylvin on M2-type macrophage activation, aiming to test the hypothesis that pinosylvin could polarize macrophages from M1 to M2 phenotype to support resolution of inflammation. We used lipopolysaccharide (LPS) to induce M1 phenotype and interleukin-4 (IL-4) to induce M2 phenotype in J774 murine and U937 human macrophages, and we measured expression of M1 and M2-markers. Interestingly, along with inhibiting the expression of M1-type markers, pinosylvin had an enhancing effect on the M2-type activation, shown as an increased expression of arginase-1 (Arg-1) and mannose receptor C type 1 (MRC1) in murine macrophages, and C-C motif chemokine ligands 17 and 26 (CCL17 and CCL26) in human macrophages. In IL-4-treated macrophages, pinosylvin enhanced PPAR-γ expression but had no effect on STAT6 phosphorylation. The results show, for the first time, that pinosylvin shifts macrophage polarization from the pro-inflammatory M1 phenotype towards M2 phenotype, supporting resolution of inflammation and repair.

Aim: The aim of this study was to investigate inflammatory and respiratory responses to welding fume exposure in patients with suspected occupational asthma. Methods: Sixteen patients referred to the Finnish Institute of Occupational Health underwent mild steel (MS) and stainless steel (SS) welding challenge tests, due to suspicion of OA. Platelet count, leucocytes and their differential count, hemoglobin, sensitive CRP, lipids, glucose and fibrinogen were analyzed in addition to interleukin (IL)-1β, IL-6, IL-8, TNF-α, endothelin-1, and E-selectin in plasma samples. Peak expiratory flow (PEF), forced expiratory volume in 1 min (FEV1) and exhaled nitric oxide (NO) measurements were performed before and after the challenge test. Personal particle exposure was assessed using IOM and a mini sampler. Particle size distribution was measured by an Electric Low Pressure Impactor (ELPI). Results: The number of leukocytes, neutrophils, and platelets increased significantly, and the hemoglobin level and number of erythrocytes decreased significantly after both the MS and SS exposure tests. Five of the patients were diagnosed with OA, and their maximum fall in FEV1 values was 0.70 l (±0.32) 4 h after SS exposure. MS welding generated an average inhalable particle mass concentration of 31.6, and SS welding of 40.2 mg/m3. The mean particle concentration measured inside the welding face shields by the mini sampler was 30.2 mg/m3 and 41.7 mg/m3, respectively. Conclusions: Exposure to MS and SS welding fume resulted in a mild systemic inflammatory response. The particle concentration from the breathing zones correlated with the measurements inside the welding face shields.

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme situated downstream of cyclo-oxygenase-2, promoting the excessive PGE2 production in inflammation. Dexamethasone is known to suppress mPGES-1 but the mechanisms regulating mPGES-1 expression remain poorly known. MKP-1 is a phosphatase controlling the proinflammatory MAP kinase pathways p38 and JNK, thus limiting the inflammatory responses. We have now investigated the role of MKP-1 and MAP kinases p38 and JNK in the regulation of mPGES-1 expression by dexamethasone. Dexamethasone increased MKP-1 and decreased mPGES-1 expression in J774 macrophages and in peritoneal macrophages from wild-type but not from MKP-1 deficient mice. Dexamethasone also reduced p38 and JNK phosphorylation along with enhancement of MKP-1, while inhibition of JNK reduced mPGES-1 expression. These findings were also translated to in vivo conditions as dexamethasone downregulated mPGES-1 expression in paw inflammation in wild-type but not in MKP-1 deficient mice. In conclusion, dexamethasone was found to downregulate mPGES-1 expression through enhanced MKP-1 expression and reduced JNK phosphorylation in inflammatory conditions. The results extend the understanding on the regulation of mPGES-1 expression and highlight the potential of MKP-1 as an anti-inflammatory drug target.

YKL-40, a chitinase-like glycoprotein associated with inflammation and tissue remodeling, is produced by joint tissues and recognized as a candidate auto-antigen in rheumatoid arthritis (RA). In the present study, we investigated YKL-40 as a potential biomarker of disease activity in patients with early RA at baseline and during intensive treatment aiming for early remission.Ninety-nine patients with early DMARD-naïve RA participated in the NEO-RACo study. For the first four weeks, the patients were treated with the combination of sulphasalazine, methotrexate, hydroxychloroquine and low dose prednisolone (FIN-RACo DMARD combination), and subsequently randomized to receive placebo or infliximab added on the treatment for further 22 weeks. Disease activity was evaluated using the 28-joint disease activity score and plasma YKL-40 concentrations were measured by immunoassay.At the baseline, plasma YKL-40 concentration was 57 ± 37 (mean ± SD) ng/ml. YKL-40 was significantly associated with the disease activity score, interleukin-6 and erythrocyte sedimentation rate both at the baseline and during the 26 weeks' treatment. The csDMARD combination decreased YKL-40 levels already during the first four weeks of treatment, and there was no further reduction when the tumour necrosis factor-α antagonist infliximab was added on the combination treatment.High YKL-40 levels were found to be associated with disease activity in early DMARD-naïve RA and during intensive treat-to-target therapy. The present results suggest YKL-40 as a useful biomarker of disease activity in RA to be used to steer treatment towards remission.

YKL-40 is a chitinase-like glycoprotein produced by alternatively activated macrophages that are associated with wound healing and fibrosis. Asbestosis is a chronic asbestos-induced lung disease, in which injury of epithelial cells and activation of alveolar macrophages lead to enhanced collagen production and fibrosis. We studied if YKL-40 is related to inflammation, fibrosis, and/or lung function in subjects exposed to asbestosis. Venous blood samples were collected from 85 men with moderate or heavy occupational asbestos exposure and from 28 healthy, age-matched controls. Levels of plasma YKL-40, CRP, IL-6, adipsin, and MMP-9 were measured with enzyme-linked immunosorbent assay (ELISA). Plasma YKL-40 levels were significantly higher in subjects with asbestosis (n=19) than in those with no fibrotic findings in HRCT following asbestos exposure (n=66) or in unexposed healthy controls. In asbestos-exposed subjects, plasma YKL-40 correlated negatively with lung function capacity parameters FVC (Pearson’s r −0.259, p=0.018) and FEV1 (Pearson’s r −0.240, p=0.028) and positively with CRP (Spearman’s rho 0.371, p

Objectives: We aimed to study if interleukin (IL) 8 and hepatocyte growth factor (HGF) predict development of severe acute pancreatitis (SAP) among patients without organ dysfunction (OD) at presentation, and if they discriminate transient OD from persistent OD among patients presenting with OD. Methods: From prospectively collected cohort of 176 AP patients and 32 healthy controls, plasma levels of IL-8 and HGF were determined within 5 days after symptom onset using an enzyme-linked immunosorbent assay. Results: AP was severe in 23 patients, of whom 10 did not have clinical signs of OD at presentation. IL-8 and HGF levels increased along with the severity of AP (P

Most cases of hemorrhagic fever with renal syndrome (HFRS) in Europe are caused by the Puumala hantavirus (PUUV). Typical features of the disease are increased vascular permeability, acute kidney injury (AKI), and thrombocytopenia. YKL-40 is an inflammatory glycoprotein involved in various forms of acute and chronic inflammation. In the present study, we examined plasma YKL-40 levels and the associations of YKL-40 with disease severity in acute PUUV infection. A total of 79 patients treated in Tampere University Hospital during 2005−2014 were studied. Plasma YKL-40 was measured in the acute phase, the recovery phase, and one year after hospitalization. Plasma YKL-40 levels were higher during the acute phase compared to the recovery phase and one year after hospitalization (median YKL-40 142 ng/mL, range 11−3320, vs. 45 ng/mL, range 15−529, vs. 32 ng/mL, range 3−213, p < 0.001). YKL-40 level was correlated with the length of hospital stay (r = 0.229, p = 0.042), the levels of inflammatory markers—that is, blood leukocytes (r = 0.234, p = 0.040), plasma C-reactive protein (r = 0.332, p = 0.003), and interleukin-6 (r = 0.544, p < 0.001), and maximum plasma creatinine level (r = 0.370, p = 0.001). In conclusion, plasma YKL-40 levels were found to be elevated during acute PUUV infection and correlated with the overall severity of the disease, as well as with the degree of inflammation and the severity of AKI.

Objectives: To investigate cardiorespiratory and inflammatory responses in male workers following exposure to welding fumes and airborne particles in actual workplace conditions. Materials and Methods: We measured blood leukocytes and their differential counts, platelet count, hemoglobin, sensitive C-reactive protein, fibrinogen, E-selectin, IL-(interleukin)1β, IL-6, IL-8, tumor necrosis factor alpha (TNF-α) and endothelin-1 in blood samples of twenty workers before and after their working day. We also studied peak expiratory flow (PEF), forced expiratory volume in one second (FEV1), and exhaled nitric oxide (NO). We assessed heart rate variability (HRV) by obtaining 24-hour ambulatory electrocardiograms. Results: The total blood leukocytes and neutrophils increased after the work shift, whereas IL-1β and E-selectin decreased significantly. There were no tatistically significant changes in exhaled NO, FEV1, PEF or HRV. Conclusion: Occupational exposure to welding fumes and particles caused a slight, acute inflammatory effect estimated based on the increased values of leukocytes and neutrophils in blood and a decrease in the interleukin 1β and E-selectin values, but no changes in the pulmonary function (exhaled NO, FEV1, PEF) or HRV during the working day were observed.

This study evaluated nutrition and growth in relation to plasma adipokine levels in 21 very-low-birth-weight (VLBW) children with radiographic bronchopulmonary dysplasia (BPD), 19 VLBW controls, and 19 term controls with a median age of 11.3 years. We took anthropometric measurements; assessed plasma levels of adipsin, resistin, adiponectin, and leptin; and analyzed the children’s 3-day food records. Children with BPD had a smaller age-adjusted head circumference and more microcephaly but no other significant growth differences. Daily recommended nutritional intake levels were poorly met but did not differ between the groups. Leptin levels correlated positively with the body mass index standard deviation score in VLBW children. No other associations between adipokine concentrations and growth were found. There were negative correlations between leptin concentrations and fat intake, resistin levels and carbohydrate intake, and adiponectin, adipsin, and leptin levels and energy intake.

INTRODUCTION:Hip arthroplasty is the standard treatment of a painful hip destruction. The use of modern metal-on-metal (MOM) bearing surfaces gained popularity in total hip arthroplasties during the last decade. Recently, worrisome failures due to adverse reaction to metal debris (ARMD), including pseudotumor response, have been widely reported. However, the pathogenesis of this reaction remains poorly understood. The aim of the present study was to investigate the ARMD response by flow cytometry approach. METHODS:Sixteen patients with a failed Articular Surface Replacement (ASR) hip prosthesis were included in the study. Samples of pseudotumor tissues collected during revision surgery were degraded by enzyme digestion and cells were typed by flow cytometry. Whole blood chromium and cobalt concentrations were analyzed with mass spectrometry before revision surgery. RESULTS:Flow cytometry analysis showed that the peri-implant pseudotumor tissue expressed two principal phenotypes, namely macrophage-dominated and T-lymphocyte-dominated response; the average portions being 54% (macrophages) and 25% (T-lymphocytes) in macrophage-dominated inflammation and 20% (macrophages) and 54% (T-lymphocytes) in T-lymphocyte-dominated response. The percentages of B-lymphocytes and granulocytes were lower in both phenotypes. Interestingly, the levels of blood chromium and cobalt were significantly higher in patients with macrophage-dominated response. CONCLUSIONS:The results suggest that the adverse tissue reactions induced by MOM wear particles contain heterogeneous pathogeneses and that the metal levels are an important factor in the determination of the inflammatory phenotype. The present results support the hypothesis that higher metal levels cause cytotoxicity and tissue injury and macrophages are recruited to clear the necrotic debris. On the other hand, the adverse response developed in association with lower metal levels is T-lymphocyte-dominated and is likely to reflect hypersensitivity reaction.

Several biomarkers for early detection of severe acute pancreatitis (SAP) have been presented. Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) are released early in inflammation. We aimed to assess levels of MMP-7, -8, -9 and TIMP-1 in acute pancreatitis (AP) and explore their ability to detect disease severity. Our second aim was to find an association between MMPs, TIMP and creatinine.We collected plasma samples for MMP-7, -8, -9 and TIMP-1 analyses from 176 patients presenting within 96 h from onset of acute pancreatitis (AP) symptoms. We used samples from 32 control subjects as comparison. The revised Atlanta Classification was utilised to assess severity of disease. Receiver operating characteristic curve analysis and Spearman´s Rho-test were utilised for statistical calculations.Compared with controls, patients showed higher levels of all studied markers. MMP-8 was higher in moderately severe AP than in mild AP (p = 0.005) and MMP-8, -9 and TIMP-1 were higher in severe than in mild AP (p

Mitogen-activated protein kinase phosphatase 1 (MKP-1) expression is induced by inflammatory factors, and it is an endogenous suppressor of inflammatory response. MKP-1 expression is increased by PDE4 inhibitor rolipram suggesting that it is regulated by cAMP-enhancing compounds. Therefore, we investigated the effect of β2-receptor agonists on MKP-1 expression and inflammatory response. We found that β2-receptor agonists salbutamol and terbutaline, as well as 8-Br-cAMP, increased MKP-1 expression. Salbutamol and terbutaline also inhibited p38 MAPK phosphorylation and TNF production in J774 mouse macrophages. Interestingly, salbutamol suppressed carrageenan-induced paw inflammation in wild-type mice, but the effect was attenuated in MKP-1(-/-) mice. In conclusion, these data show that β2-receptor agonists increase MKP-1 expression, which seems to mediate, at least partly, the observed anti-inflammatory effects of β2-receptor agonists.

Interleukin-6 (IL-6) is involved in the pathogenesis of various inflammatory diseases, like rheumatoid arthritis (RA). In the present study, we investigated the role of IL-6 in osteoarthritis (OA) patients and the effects of the stilbenoids monomethyl pinosylvin and pinosylvin on the expression of the cartilage matrix components aggrecan and collagen II and the inflammatory cytokine IL-6 in human OA chondrocytes. Synovial fluid and plasma samples were obtained from 100 patients with severe OA [BMI 29.7 (8.3) kg/m2, age 72 (14) years, median (IQR); 62/38 females/males] undergoing total knee replacement surgery. IL-6 and matrix metalloproteinase (MMP) concentrations in synovial fluid and plasma were measured by immunoassay. The effects of pinosylvin on the expression of IL-6, aggrecan, and collagen II were studied in primary cultures of human OA chondrocytes. IL-6 levels in synovial fluid from OA patients [119.8 (193.5) pg/mL, median (IQR)] were significantly increased as compared to the plasma levels [3.1 (2.7) pg/mL, median (IQR)] and IL-6 levels in synovial fluid were associated with MMPs and radiographic disease severity. Natural stilbenoids monomethyl pinosylvin and pinosylvin increased aggrecan expression and suppressed IL-6 production in OA chondrocytes. The results propose that IL-6 is produced within OA joints and has an important role in the pathogenesis of OA. Stilbenoid compounds monomethyl pinosylvin and pinosylvin appeared to have disease-modifying potential in OA chondrocytes.

Background and Objective. The role of adipokines in regulation of immune responses has been recognized, but very little is known about their impact on multiple sclerosis (MS). In this study, we analysed whether the major adipokines are differentially expressed in plasma of patients with different MS subtypes and clinically isolated syndrome (CIS) and explored their association with major disease characteristics. Methods. The levels of adiponectin, adipsin, leptin, and resistin in the plasma of 80 patients with different subtypes of MS and CIS were followed up annually over the two years. The data obtained were correlated with disease activity, EDSS and volumes of T1-weighted lesions (T1-LV), and fluid attenuation inversion recovery lesions (FLAIR-LV) on MRI. Results. In MS group, a correlation was found between the level of adipsin and EDSS score at baseline (r=0.506, p

INTRODUCTION:In gout, monosodium urate (MSU) crystals deposit intra-articularly and cause painful arthritis. In the present study we tested the hypothesis that Transient Receptor Poten-tial Ankyrin 1 (TRPA1), an ion channel mediating nociceptive signals and neurogenic in-flammation, is involved in MSU crystal-induced responses in gout by utilizing three experi-mental murine models. METHODS:The effects of selective pharmacological inhibition (by HC-030031) and genetic depletion of TRPA1 were studied in MSU crystal-induced inflammation and pain by using 1) spontaneous weight-bearing test to assess MSU crystal-induced joint pain, 2) subcutaneous air-pouch model resembling joint inflammation to measure MSU crystal-induced cytokine production and inflammatory cell accumulation, and 3) MSU crystal-induced paw edema to assess acute vascular inflammatory responses and swelling. RESULTS:Intra-articularly injected MSU crystals provoked spontaneous weight shift off from the affected limb in wild type but not in TRPA1 knock-out mice referring alleviated joint pain in TRPA1 deficient animals. MSU crystal-induced inflammatory cell infiltration and accumulation of cytokines MCP-1, IL-6, IL-1beta, MPO, MIP-1alpha and MIP-2 into subcu-taneous air-pouch (resembling joint cavity) was attenuated in TRPA1 deficient mice and in mice treated with the selective TRPA1 inhibitor HC-030031 as compared to control animals. Further, HC-030031 treated and TRPA1 deficient mice developed tempered inflammatory edema when MSU crystals were injected into the paw. CONCLUSIONS:TRPA1 mediates MSU crystal-induced inflammation and pain in experimental models supporting the role of TRPA1 as a potential mediator and a drug target in gout flare.

The aim of the present study was to examine constitutive signal transducer and activator of transcription 3 (STAT3) phosphorylation in circulating leukocytes as a candidate biomarker in rheumatoid arthritis (RA). 25 patients with recent-onset, untreated RA provided samples for whole blood flow cytometric determination of intracellular STAT3 phosphorylation, expressed as relative fluorescence units. The occurrence of constitutive STAT3 phosphorylation was evaluated by determining proportion of STAT3-phosphorylated cells among different leukocyte subtypes. Plasma levels of interleukin (IL)-6, IL-17 and IL-21 were measured by immunoassay, radiographs of hands and feet were examined and disease activity score (DAS28) was determined. Biomarkers were restudied and treatment response (according to European League Against Rheumatism) was determined after 12 months of treatment with disease-modifying antirheumatic drugs. At baseline, constitutive phosphorylation of STAT3 occurred in CD4+ T cells of 14 (56%) patients, CD8+ T cells of 13 (52%) patients, in CD19+ B cells of 7 (28%) patients, and in CD14+ monocytes of 12 (48%) patients. STAT3 phosphorylation levels of CD4+ T cells associated with DAS28, and those of all leukocyte subtypes studied associated with erosive disease. The presence of constitutive STAT3 phosphorylation in CD4+ T lymphocytes, pSTAT3 fluorescence intensity of CD4+ and CD8+ T cells and C-reactive protein (CRP) levels at baseline associated with good treatment response. In conclusion, constitutive STAT3 phosphorylation in circulating CD4+ T cells is common in recent-onset untreated RA and associates with good treatment response in patients characterized by high disease activity and the presence of systemic inflammation.

YKL-40 is associated with tissue injury and inflammation, and consequently to diseases in which these mechanisms lead to tissue degradation, for example, asthma and rheumatoid arthritis. The purpose of the present study was to investigate if YKL-40 is also a significant factor in osteoarthritis (OA) by assessing associations of YKL-40 with mediators related to the pathogenesis of OA: cartilage destructing matrix metalloproteinases (MMPs) and proinflammatory cytokines interleukin-6 (IL-6) and interleukin-17 (IL-17). Cartilage, synovial fluid (SF), and plasma samples were obtained from 100 OA patients undergoing total knee replacement surgery. SF levels of YKL-40 (1027.9 ± 78.3 ng/mL) were considerably higher than plasma levels (67.2 ± 4.5 ng/mL) and correlated with YKL-40 released from cartilage samples obtained from the same patients (r=0.37, P=0.010), indicating that YKL-40 is produced by OA cartilage. Interestingly, YKL-40 concentrations in OA SF correlated positively with MMP-1 (r=0.36, P=0.014), MMP-3 (r=0.46, P=0.001), IL-6 (r=0.57, P

Eosinophils play a central role in asthma. The present study was performed to investigate the effect of tumour necrosis factor-α (TNF-α) on longevity of isolated human eosinophils. In contrast to Fas, TNF-α inhibited eosinophil apoptosis as evidenced by a combination of flow cytometry, DNA fragmentation assay and morphological analyses. The effect of TNF-α on eosinophil apoptosis was reversed by a TNF-α neutralising antibody. The anti-apoptotic effect of TNF-α was not due to autocrine release of known survival-prolonging cytokines interleukins 3 and 5 or granulocyte-macrophage-colony-stimulating factor as their neutralisation did not affect the effect of TNF-α. The anti-apoptotic signal was mediated mainly by the TNF-receptor 1. TNF-α induced phosphorylation and degradation of IκB and an increase in NF-κB DNA-binding activity. The survival-prolonging effect of TNF-α was reversed by inhibitors of NF-κB pyrrolidinedithiocarbamate and gliotoxin and by an inhibitor of IκB kinase, BMS-345541. TNF-α induced also an increase in AP-1 DNA-binding activity and the antiapoptotic effect of TNF-α was potentiated by inhibitors of AP-1, SR 11302 and tanshinone IIA and by an inhibitor of c-jun-N-terminal kinase, SP600125, which is an upstream kinase activating AP-1. Our results thus suggest that TNF-α delays human eosinophil apoptosis via TNF-receptor 1 and the resulting changes in longevity depend on yin-yang balance between activation of NF-κB and AP-1.

Running a marathon causes strenuous joint loading and increased energy expenditure. Adipokines regulate energy metabolism, but recent studies have indicated that they also exert a role in cartilage degradation in arthritis. Our aim was to investigate the effects of running a marathon on the levels of adipokines and indices of cartilage metabolism. Blood samples were obtained from 46 male marathoners before and after a marathon run. We measured levels of matrix metalloproteinase-3 (MMP-3), cartilage oligomeric protein (COMP) and chitinase 3-like protein 1 (YKL-40) as biomarkers of cartilage turnover and/or damage and plasma concentrations of adipokines adiponectin, leptin and resistin. Mean marathon time was 3:30:46±0:02:46 (h:min:sec). The exertion more than doubled MMP-3 levels and this change correlated negatively with the marathon time (r = -0.448, p = 0.002). YKL-40 levels increased by 56% and the effect on COMP release was variable. Running a marathon increased the levels of resistin and adiponectin, while leptin levels remained unchanged. The marathon-induced changes in resistin levels were positively associated with the changes in MMP-3 (r = 0.382, p = 0.009) and YKL-40 (r = 0.588, p

In inflammation, pro-inflammatory cytokines and bacterial products induce the production of high amounts of NO by inducible nitric oxide synthase (iNOS) in inflammatory and tissue cells. NO is an effector molecule in innate immunity, and it also has regulatory and pro-inflammatory/destructive effects in the inflammatory process. Protein kinase Cδ (PKCδ) is an important signaling protein regulating B lymphocyte functions, but less is known about its effects in innate immunity and inflammatory gene expression. In the present study we investigated the role of PKCδ in the regulation of iNOS expression in inflammatory conditions. NO production and iNOS expression were induced by LPS or a combination of cytokines IFNγ, IL-1β, and TNFα. Down-regulation of PKCδ by siRNA and inhibition of PKCδ by rottlerin suppressed NO production and iNOS expression in activated macrophages and fibroblasts. PKCδ directed siRNA and inhibition of PKCδ by rottlerin suppressed also the expression of transcription factor IRF1, possibly through inhibition of STAT1 activation. Accordingly, down-regulation of IRF1 by siRNA reduced iNOS expression in response to inflammatory stimuli. In addition, inhibition of PKCδ showed anti-inflammatory effects in carrageenan induced paw inflammation in mice as did iNOS inhibitor L-NIL. These results suggest that inhibitors of PKCδ have anti-inflammatory effects in disease states complicated by enhanced NO production through iNOS pathway.

The study aimed to determine the effect of the activated protein C on the course of systemic inflammation in the APCAP (activated protein C in acute pancreatitis) trial where we randomized 32 patients with severe acute pancreatitis to receive either recombinant activated protein C (drotrecogin alfa activated) (n=16) or placebo (n=16) for 96 hours. In the present study, we present the time course of the patients’ plasma or serum levels of soluble markers (IL-8, IL-6, IL-10, IL-1ra, sE-selectin, PCT) and monocyte and neutrophil cell surface (CD11b, CD14, CD62L, HLA-DR) markers of systemic inflammatory response during the first 14 days after the randomization. The results of the intervention and placebo groups were comparable showing that recombinant APC treatment did not alter the course of systemic inflammation in severe acute pancreatitis. Our finding is in accordance with the clinical findings in the APCAP trial indicating that the intervention did not affect evolution of multiple organ dysfunctions.

The role of dual specificity phosphatase 1 (DUSP1) in inducible nitric oxide synthase (iNOS) expression in A549 human pulmonary epithelial cells, J774 mouse macrophages and primary mouse bone marrow-derived macrophages (BMMs) was investigated. iNOS expression was induced by a cytokine mixture (TNF, IFNγ and IL-1β) in A549 cells and by LPS in J774 cells, and it was inhibited by p38 MAPK inhibitors SB202190 and BIRB 796. Stimulation with cytokine mixture or LPS enhanced also DUSP1 expression. Down-regulation of DUSP1 by siRNA increased p38 MAPK phosphorylation and iNOS expression in A549 and J774 cells. In addition, LPS-induced iNOS expression was enhanced in BMMs from DUSP1(−/−) mice as compared to that in BMMs from wild-type mice. The results indicate that DUSP1 suppresses iNOS expression by limiting p38 MAPK activity in human and mouse cells. Compounds that enhance DUSP1 expression or modulate its function may be beneficial in diseases complicated with increased iNOS-mediated NO production.

Obesity is an important risk factor for osteoarthritis (OA) in weight-bearing joints, but also in hand joints, pointing to an obesity-related metabolic factor that influences on the pathogenesis of OA. Leptin is an adipokine regulating energy balance, and it has recently been related also to arthritis and inflammation as a proinflammatory factor. In the present paper, the effects of leptin on human OA cartilage were studied. Leptin alone or in combination with IL-1 enhanced the expression of iNOS and COX-2, and production of NO, PGE2, IL-6, and IL-8. The results suggest that the effects of leptin are mediated through activation of transcription factor nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway c-Jun NH2-terminal kinase (JNK). Interestingly, inhibition of leptin-induced NO production with a selective iNOS inhibitor 1400 W inhibited also the production of IL-6, IL-8, and PGE2, and this was reversed by exogenously added NO-donor SNAP, suggesting that the effects of leptin on IL-6, IL-8, and PGE2 production are dependent on NO. These findings support the idea of leptin as a factor enhancing the production of proinflammatory factors in OA cartilage and as an agent contributing to the obesity-associated increased risk for osteoarthritis.

In inflammation, bacterial products and proinflammatory cytokines induce the formation of large amounts of nitric oxide (NO) by inducible nitric oxide synthase (iNOS), and compounds that inhibit NO production have anti-inflammatory effects. In the present study, we systematically investigated the effects of 36 naturally occurring flavonoids and related compounds on NO production in macrophages exposed to an inflammatory stimulus (lipopolysaccharide, LPS), and evaluated the mechanisms of action of the effective compounds. Flavone, the isoflavones daidzein and genistein, the flavonols isorhamnetin, kaempferol and quercetin, the flavanone naringenin, and the anthocyanin pelargonidin inhibited iNOS protein and mRNA expression and also NO production in a dose-dependent manner. All eight active compounds inhibited the activation of nuclear factor-κB (NF-κB), which is a significant transcription factor for iNOS. Genistein, kaempferol, quercetin, and daidzein also inhibited the activation of the signal transducer and activator of transcription 1 (STAT-1), another important transcription factor for iNOS. The present study characterises the effects and mechanisms of naturally occurring phenolic compounds on iNOS expression and NO production in activated macrophages. The results partially explain the pharmacological efficacy of flavonoids as anti-inflammatory compounds.

In inflammation, the post-transcriptional regulation of transiently expressed genes provides a potential therapeutic target. Tristetraprolin (TTP) is of the factors regulating decay of cytokine mRNAs. The aim of the present study was to identify cytokines whose expression is regulated by TTP. We established a TTP knock-down cell line by expressing shRNA against TTP (shTTP cell line). A cytokine antibody array was used to measure cytokine production in macrophages exposed to lipopolysaccharide (LPS). Cytokines IL-6, IL-12, TNF-α, and MIP-2 (a homologue to human IL-8) were expressed at higher levels whereas MIP-3α was produced at lower levels in LPS-treated shTTP cells than in control cells suggesting that the expression of these cytokines is regulated by TTP. The present data provide IL-12, MIP-2, and MIP-3α as novel inflammatory cytokine targets for TTP-mediated mRNA decay and stress the role of TTP in the regulation of the inflammatory process.

In inflammation, inducible nitric oxide synthase (iNOS) produces nitric oxide (NO), which modulates inflammatory processes. We investigated the effects of Janus kinase (JAK) inhibitors, AG-490 and WHI-P154, on iNOS expression and NO production in J774 murine macrophages stimulated with interferon-γ (IFN-γ). JAK inhibitors AG-490 and WHI-P154 decreased IFN-γ-induced nuclear levels of signal transducer and activator of transcription 1α (STAT1α). JAK inhibitors AG-490 and WHI-P154 decreased also iNOS protein and mRNA expression and NO production in a concentration-dependent manner. Neither of the JAK inhibitors affected the decay of iNOS mRNA when determined by actinomycin D assay. Our results suggest that the inhibition of JAK-STAT1-pathway by AG-490 or WHI-P154 leads to the attenuation of iNOS expression and NO production in IFN-γ-stimulated macrophages.