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Background/Aims To elucidate the role of systemic inflammation in nonalcoholic fatty liver disease (NAFLD). Methods Serum samples in 47 patients with histologically verified NAFLD (22 with simple steatosis and 25 with nonalcoholic steatohepatitis [NASH]), and in 30 age-, sex- and ethnicity-matched healthy controls, were assessed for (i) general markers of inflammation (C-reactive protein [CRP], tumor necrosis factor [TNF]-α, and interleukin [IL]-6), (ii) chemokines (CC-chemokine ligand [CCL] 2/monocyte chemoattractant protein [MCP]-1, CCL19 and CCL21), (iii) adipocytokines related to insulin resistance and inflammation (adiponectin and leptin) and (iv) a marker of oxidative stress (8-isoprostane-F2α). Results Serum levels of several inflammatory cytokines were increased in NAFLD as compared to controls, and IL-6 ( P =0.017), CCL2/MCP-1 ( P =0.008) and CCL19 ( P =0.001), but not CRP ( P =0.199), remained elevated also after correction for sex, body mass index (BMI) and age. Comparing NASH with simple steatosis, levels of TNF-α ( P =0.024) and CCL2/MCP-1 ( P =0.012) were elevated and adiponectin (in women) ( P =0.001) were decreased also after adjustment for sex, BMI and presence of the metabolic syndrome. Conclusions Our results indicate that patients with NAFLD are characterized by a low-grade systemic inflammation. The high CCL2/MCP-1 levels in NASH might be of importance for the conversion from simple steatosis to NASH.

Background— Numerous studies have demonstrated the ability of oxidized LDL [(ox)LDL] to promote an inflammatory response in macrophages. Several inflammatory mediators have been reported to increase after oxLDL stimulation of such cells, but their relative importance is still unknown. In the present study, we used microarrays to identify genes in THP-1 macrophages that were upregulated by oxLDL. Methods and Results— Our main findings were as follows. In a microarray screening experiment, we identified LIGHT, a ligand in the tumor necrosis factor superfamily, as one of the genes that were markedly upregulated in oxLDL-stimulated THP-1 macrophages. We showed significantly raised plasma levels of LIGHT in patients with stable angina (n=40) and particularly in those with unstable angina (n=40) compared with healthy controls (n=20), which underscores the clinical relevance of the in vitro finding. We also showed that LIGHT enhanced lipid accumulation in oxLDL-stimulated THP-1 macrophages, possibly through upregulation of class A scavenger receptor (SR-A). This increased lipid accumulation was accompanied by enhanced expression of tissue factor and plasminogen activator inhibitor-1, as well as enhanced thrombin formation, transforming macrophages into a prothrombotic phenotype. The LIGHT-mediated increase in SR-A, tissue factor, and plasminogen activator inhibitor-1 was also seen in human monocyte-derived macrophages. Finally, the LIGHT-mediated enhancement of SR-A and TF expression appears to involve nuclear factor-κB activation. Conclusions— These findings suggest that LIGHT could serve as a molecular link between lipid metabolism, inflammation, and thrombus formation, which are all features of atherosclerotic plaques.

Evidence from both experimental and clinical trials indicates that inflammatory mediators are important in the pathogenesis of chronic heart failure (HF), contributing to cardiac remodelling and peripheral vascular disturbances. Several studies have shown raised levels of inflammatory cytokines such as TNF-alpha, IL-1beta and -6 in HF patients in plasma, circulating leukocytes, atherosclerotic lesions, and in the failing myocardium itself. Importantly, this rise in inflammatory mediators does not seem to be accompanied by a corresponding increase in anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta; thus resulting in an inflammatory imbalance in the cytokine network. Traditional cardiovascular drugs have little influence on the cytokine network in HF patients. Results from randomised, placebo-controlled anti-TNF studies suggest lack of effect of such therapy. Although somewhat disappointing, these negative results do not necessarily argue against the 'cytokine hypothesis'; these studies just underscore the challenges in understanding the complex cytokine network in order to develop effective treatment modalities in HF patients. More general immunmodulating treatments, such as pentoxyfylline, intravenous immunoglobulin, thalidomide and statins, have shown promising results in smaller studies, which need to be confirmed in larger studies with hospitalisations and death as the end points. In addition, further research in this area will have to be more precise in identifying the most important 'actors' in the immunopathogenesis of chronic HF.

Early anti-thrombotic and anti-inflammatory actions of statins and fibrates – time for adjuvant therapy in acute coronary syndromes?

Common variable immunodeficiency (CVID) is characterized by low levels of circulating immunoglobulins, leading to frequent infections, particularly of the respiratory tract. Frequently, T-cell abnormalities are observed. Interleukin-7 (IL-7) is involved in the homeostasis of lymphocytes, and may be elevated in lymphopenia. Mutations of genes related to IL-7 may lead to severe immunodeficiency disorders. We report elevated plasma levels of circulating IL-7 in a subgroup of CVID. These patients have increased numbers of circulating CD8+ T cells with decreased apoptosis and a predominance of CC chemokine receptor 7- (CCR7-) effector-memory T cells. Moreover, in some of these patients there is impaired response to IL-7 as assessed by in vitro proliferation and secretion of interferon γ and transforming growth factor β. These findings suggest novel pathogenic mechanisms and specific targets for further research in CVID.

Background: Enhanced activity of matrix metalloproteinases (MMPs) has been reported to have a pathogenic role in several diseases such as cancer and cardiovascular disorders, and seems also to play a part in certain autoimmune diseases. Objective: To examine whether enhanced MMP activity may also have a role in the pathogenesis of Wegener’s granulomatosis (WG). Methods: In a study group of 15 patients with WG and 15 controls, plasma levels and gene expression were measured in freshly isolated peripheral blood mononuclear cells (PBMCs) of several MMPs and their endogenous inhibitors (that is, tissue inhibitors of metalloproteinases (TIMPs)) by enzyme immunoassays and RNase protection assay, respectively. Results: Whereas patients with WG in remission had enhanced gene expression of several MMPs and TIMPs in PBMCs, those with active disease had a selective up regulation of MMP-2 and MMP-8 compared with healthy controls, and a down regulation of TIMP-1 and TIMP-3 compared with other patients with WG. Moreover, plasma levels of TIMP-1 and MMP-8 correlated significantly with C reactive protein levels, further supporting an association between activation of the MMP/TIMP system and disease activity in WG. Finally, these changes in MMP/TIMP expression in WG were accompanied by increased total MMP activity in PBMC supernatants, particularly in those with active disease, suggesting a matrix degrading net effect. Conclusion: These findings suggest that disturbed MMP and TIMP activity has a role in the pathogenesis of WG.

Background— Inflammatory processes seem to be involved in pulmonary arterial hypertension (PAH). CD40 ligand (L) may promote inflammation and thrombus formation, and we hypothesized that CD40L could be involved in the pathogenesis of PAH. Methods and Results— Several significant findings were revealed when examining the possible role of CD40L in PAH. (1) Patients with primary (n=13) and secondary (n=11) PAH but not those with chronic thromboembolic pulmonary hypertension (n=8) had increased plasma levels of soluble (s) CD40L compared with control subjects (n=8). (2) PAH patients using warfarin had markedly lower sCD40L levels than those without such therapy. (3) sCD40L levels were higher in arterial (femoral artery) compared with mixed venous blood (pulmonary artery), suggesting enhanced release or reduced clearance in the pulmonary vasculature. (4) Platelets from PAH patients showed enhanced spontaneous and SFLLRN-stimulated release of sCD40L compared with control subjects. (5) In vitro, recombinant sCD40L induced monocyte chemoattractant protein (MCP)-1 and interleukin-8 gene expression in endothelial cells, and plasma levels of these chemokines were raised in all PAH groups, significantly correlated to sCD40L and hemodynamic parameters. (6) Although prostacyclin therapy (3 months) showed clinical benefit, this therapy had no effect on sCD40L and increased MCP-1 levels in PAH patients, and prostacyclin enhanced MCP-1 in CD40L-stimulated endothelial cells. Conclusions— Our findings suggest a role for CD40L in the pathogenesis of PAH, possibly operating through an interaction between platelets and endothelial cells involving chemokine-related mechanisms.

An inappropriate and persistent immune activation has been suggested to contribute to long-term mortality and morbidity after heart transplantation. Several lines of evidence suggest that platelets do not only promote thrombus formation, but also act as inflammatory cells. In the present study, we investigated if long-time survivors of heart transplantation (mean time since transplantation 6.5 yr) were characterized by enhanced platelet activation as assessed by different experimental approaches. Our main findings when comparing heart transplant recipients (n = 52) and age- and sex-matched healthy controls (n = 38) were: (i) platelets from heart transplant recipients showed enhanced expression of both P-selectin and CD63 as assessed by flow cytometry; (ii) platelets from these patients also contained significantly increased levels of soluble CD40 ligand and tended to release higher levels of this cytokine upon SFLLRN stimulation as assessed by enzyme immunoassay; (iii) heart transplant recipients had increased levels of soluble P-selectin in platelet-free plasma; and (iv) the enhanced platelet activation after heart transplantation was most pronounced in those with concomitant hypertension. These findings suggest that long-term survivors of heart transplantation are characterized by enhanced activation of platelets, possibly contributing to the persistent immune activation and clinical complications in these patients.

Background—Although modulation of inflammatory processes has been suggested as a new treatment modality in heart failure (HF), our knowledge about abnormalities in the cytokine network during HF is still limited. On the basis of a previous cDNA array study examining peripheral blood mononuclear cells from HF patients, we hypothesized a role for activin A, a member of the transforming growth factor (TGF)-β superfamily, in the pathogenesis of HF.Methods and Results—This study had 4 main and novel findings. First, serum levels of activin A were significantly elevated in patients with HF (n=86) compared with healthy control subjects (n=20), with increasing levels according to disease severity as assessed by clinical, hemodynamic, and neurohormonal parameters. Second, compared with control subjects, HF patients, as determined by real-time quantitative reverse transcriptase polymer chain reaction, also had markedly increased gene expression of the activin A subunit activin βAin T cells but not in monocytes. Third, in a rat model of HF, we demonstrated a concerted induction of the gene expression of activin βAand activin receptors IA, IB, IIA, and IIB after myocardial infarction. Immunohistochemical analysis localized activin A solely to cardiomyocytes. Finally, activin A markedly increased gene expression of mediators involved in infarction healing and myocardial remodeling (ie, atrial natriuretic peptide, brain natriuretic peptide, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, transforming growth factor-β1, and monocyte chemoattractant protein-1) in neonatal rat cardiomyocytes.Conclusions—Together with our demonstration of activin A–induced gene expression in neonatal cardiomyocytes of mediators related to myocardial remodeling, the expression pattern of activin A during clinical and experimental HF suggests an involvement of this cytokine in the pathogenesis of HF.

Background and objectives: 8-Isoprostane is a marker of oxidative stress in vivo and increased plasma and urine levels are found in patients with vascular disease and in atherosclerotic plaques. Inflammatory chemokines such as interleukin (IL)-8 seem to play an important pathogenic role in atherogenesis. We therefore investigated the effects of 8-isoprostane on the expression of inflammatory chemokines with consciousness on IL-8 (mRNA and protein) in human macrophages. In addition, we studied the involvement of mitogen-activated protein kinases (ERK 1/2 and p38 MAPK) and nuclear factor-κB (NF-κB) in this process. Methods and results: 8-Isoprostane (10 μM) induced IL-8 expression (mRNA and protein), measured by real-time quantitative RT-PCR and enzyme immunoassay, respectively, in both THP-1 macrophages and human monocyte-derived macrophages. Moreover, 8-isoprostane increased mRNA expression of macrophage inflammatory protein-1α as determined by RNase protection assay. In this process, 8-isoprostane induced the activation of two major MAP-kinases; ERK 1/2 and p38 MAPK. Furthermore, the ERK 1/2 inhibitor, PD98059, and the p38 MAPK inhibitor, SB203580, markedly reduced 8-isoprostane-induced IL-8 expression (mRNA and protein), while inhibition of NF-κB activation and translocation had no significant effect on IL-8 expression. Conclusions: We show that 8-isoprostane increases IL-8 expression in human macrophages involving both ERK 1/2 and p38 MAPK, but not NF-κB signaling pathway. These findings further support a link between oxidative stress/lipid peroxidation and inflammation in human macrophages and suggest a role for 8-isoprostane in this process. This 8-isoprostane-induced chemokine expression might be involved in the pathogenesis of atherosclerosis as well as other inflammatory disorders.

Summary. CXC-chemokines may be involved in atherogenesis. Herein we examined the possible role of CXC-chemokines in the inflammatory interactions between oxidized (ox-) low-density lipoprotein (LDL), platelets and peripheral blood mononuclear cells (PBMC) in 15 patients with coronary artery disease (CAD) without ‘traditional’ risk factors and 15 carefully matched controls. Our main findings were: (a) ox-LDL stimulated the release of the CXC-chemokines interleukin (IL)-8, ENA-78 and GRO-α from PBMC, particularly in CAD. (b) In platelets, ox-LDL induced release of ENA-78 and, when combined with SFLLRN, also of GRO-α, with significantly higher response in CAD. (c) Platelet-rich plasma, especially when costimulated with ox-LDL, enhanced the release of IL-8 from PBMC, particularly in CAD patients. (d) Freshly isolated PBMC showed markedly increased IL-8 mRNA expression in CAD patients. Our findings suggest enhanced inflammatory interactions between ox-LDL, platelets and PBMC in CAD patients involving CXC-chemokine related mechanisms, possible contributing to atherogenesis in these and other CAD patients.

SUMMARY To gain further insight into the possible role of interleukin (IL)-18 in HIV-1 infection we examined serum levels of IL-18 in various clinical and immunological stages of HIV-1 infection during cross-sectional (n = 41) and longitudinal testing (n = 20) and during HAART (n = 21, 24 months follow-up). Our main findings were that HIV-1-infected patients had significantly raised IL-18 levels comparing healthy controls, particularly in those with advanced disease, that while HAART induced a marked decline in IL-18, virological treatment failure was associated with persistently raised IL-18 levels during such therapy and that our in vitro experiments showed an IL-18-mediated up-regulation of the HIV-1 coreceptor CXCR4 and the pro-apoptotic mediator TRAIL in PBMC from HIV-1-infected patients receiving HAART. HIV-1 infection appears to be characterized by persistently raised IL-18 levels and during HAART, such a pattern was associated with virological treatment failure, possibly contributing to immunodeficiency and HIV-1 replication in these patients.

Accumulating evidence indicates that inflammatory cytokines play a pathogenic role in congestive heart failure (CHF) by influencing heart contractility, inducing hypertrophy and promoting apoptosis or fibrosis, contributing to the continuous myocardial remodelling process. Traditional cardiovascular drugs seem to have little influence on the overall cytokine network, and immunomodulatory therapy have emerged as a possible new treatment modality in CHF. Several animal studies have suggested that modulation of inflammatory cytokines may improve cardiac performance, and we have recently demonstrated that intravenous immunoglobulin enhances left ventricular ejection fraction in CHF patients, significantly correlated with anti-inflammatory effects of such therapy. While not necessarily the drugs of choice, these studies suggest a potential for immunomodulatory therapy in CHF in addition to optimal cardiovascular treatment regimens. Further research will have to more precisely identify the most important actors in the immunopathogenesis of CHF in order to develop more specific immunomodulating agents in this disorder. Although these shortcomings, we believe that the 'cytokine era' in cardiovascular research might lead to quite new treatment modalities in CHF patients potentially leading to reduced morbidity and mortality in these patients.

Background— Atherogenesis and plaque destabilization involve immune-mediated mechanisms, but the actual mediators have not been fully clarified. Interleukin (IL)-7 is a regulator of T-cell homeostasis but also may be involved in inflammation. We hypothesized that IL-7 could be involved in the inflammatory processes observed in atherosclerosis and acute coronary syndromes. Methods and Results— To study the role of IL-7 in coronary artery disease, we analyzed IL-7 levels and the effect of this cytokine on inflammatory mediators in patients with stable and unstable angina and in healthy control subjects. Our major findings were (1) Plasma levels of IL-7 were significantly increased in patients with stable (n=30) and unstable angina (n=30) comparing healthy control subjects (n=20), particularly in those with unstable disease. (2) Increased release from activated platelets appeared to be a major contributor to the raised IL-7 levels in patients with angina. (3) IL-7 enhanced the expression of several inflammatory chemokines in peripheral blood mononuclear cells from both healthy control subjects and patients with angina, particularly in those with unstable disease. Similar effects were seen in monocytes but not in T cells. (4) MIP-1α further increased the release of IL-7 from platelets in a dose-dependent manner. (5) Aspirin reduced both the spontaneous and the SFLLRN-stimulated release of IL-7 from platelets, and when administered to healthy control subjects for 7 days (160 mg qd), it reduced plasma levels of IL-7. Conclusions— Our findings suggest a role for IL-7-driven inflammation in atherogenesis and the promotion of clinical instability in coronary artery disease involving interactions between platelets, monocytes, and chemokines.

Objectives We sought to investigate whether the activation of the chemokine network observed in patients with coronary artery disease (CAD) could be modified by treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Background Chemokines and chemokine receptors are important mediators in atherogenesis, and we hypothesized that the statins could affect the chemokine network in CAD. Methods Thirty CAD patients without previous statin therapy were randomized to receive atorvastatin (80 mg/day, n = 15) or simvastatin (20 mg/day, n = 15). Peripheral blood mononuclear cells (PBMCs) and plasma were obtained at baseline and after six months of statin therapy. Messenger ribonucleic acid (mRNA) expression of chemokines and chemokine receptors in PBMCs was analyzed by ribonuclease protection assay and real-time reverse-transcription polymerase chain reaction. Chemokines were also examined in the supernatants from unstimulated and lipopolysaccharide-stimulated PBMCs (and in plasma). Results Our main findings were: 1) gene expression of several chemokines (i.e., macrophage inflammatory protein [MIP]-1α, MIP-1β, and interleukin [IL]-8) and chemokine receptors (i.e., CC chemokine receptor [CCR]1, CCR2, CCR4, and CCR5) was markedly increased among CAD patients compared with healthy control subjects; 2) treatment with atorvastatin and simvastatin markedly reduced the mRNA levels of some of these chemokines (i.e., MIP-1α, MIP-1β, IL-8) and receptors (i.e., CCR1 and CCR2), with the most pronounced effect in the atorvastatin group; and 3) statin therapy reduced the spontaneous release of IL-8 and MIP-1α from PBMCs in CAD patients. Conclusions This study demonstrates a down-regulatory effect of statins on the chemokine network in CAD patients, possibly contributing to the beneficial effects of statins in this disorder.

Accumulating evidence indicates that inflammatory cytokines play a pathogenic role in congestive heart failure (CHF) by influencing heart contractility, inducing hypertrophy, and promoting apoptosis or fibrosis, contributing to the continuous myocardial remodeling process. Traditional cardiovascular drugs seem to have little influence on the overall cytokine network, and immunomodulatory therapy has emerged as a possible new treatment modality in CHF. Several animal studies have suggested that modulation of inflammatory cytokines may improve cardiac performance. The authors have recently demonstrated that intravenous immunoglobulin enhances the left ventricular ejection fraction in CHF patients, and that this is significantly correlated with anti-inflammatory effects of such therapy. While intravenous immunoglobulin is not necessarily the drug of choice, this study suggests a potential role for immunomodulatory therapy in CHF in addition to optimal cardiovascular treatment regimens. Further research will more precisely identify the most important actors in the immunopathogenesis of CHF and contribute to the development of more specific immunomodulating agents for this disorder.

Summary We examined the effect of interferon (IFN)-α on the expression of 375 genes relevant to inflammatory and immunological reactions in peripheral blood mononuclear cells (PBMC) from HIV-infected patients by cDNA expression array and real-time quantitative RT-PCR. Our main findings were: (i) IFN-α induced up-regulation of several genes in the tumour necrosis factor (TNF) superfamily including the ligands APRIL, FasL, TNF-α and TRAIL, with particularly enhancing effects on the latter in HIV-infected patients. (ii) While IFN-α markedly up-regulated the expression of anti-angionetic ELR– CXC-chemokines (e.g. MIG and IP-10), it suppressed the expression of angiogenic ELR+ CXC-chemokines (e.g. GRO-α, IL-8 and ENA-78), with similar patterns in both patients and controls. (iii) IFN-α induced a marked increase in gene expression of the HIV co-receptor CCR5 in both patients and controls. We suggest that these effects may contribute to both the therapeutic and toxic effects of IFN-α. Moreover, our findings underscore that the biological effects of IFN-α in HIV infection are complex and that the clinical net effects of IFN-α treatment may be difficult to predict. However, the potent enhancing effect of IFN-α on several pro-apoptotic genes in the TNF superfamily and the enhancing effect on CCR5 expression suggest a possible pathogenic role of IFN-α in the progression of HIV-related immunodeficiency and suggests caution in the therapeutic use of IFN-α in HIV-infected ­individuals.

presence of myofibroblasts in all layers of the intestinal wall. Ulcerative colitis (UC) is classically considered to be a purely mucosal disease although rarely transmural complications such as strictures and stenosis develop. Fibrogenesis in UC has not been studied systematically yet and may be a neglected phenomenon. We therefore investigated whether there is a different fibrotic load in acute vs longstanding UC and whether the degree of fibrosis in UC correlates with the severity of inflammation. Methods: Colectomy specimens from all UC patients operated at the AMC between 2007 2012 were reviewed. Specimens from patients with recent onset refractory therapy UC (diagnosis 10 years) were selected. Patients operated for colon cancer without UC served as controls. On HE 29% vs 33% vs 54%, p = 0.009). Between acute and late UC there was no difference in collagen deposition, however between UC together and controls there was more collagen I expression in the mucosa, MM and muscularis externa (50% vs 10%, p = 0.02; 28% vs 10%, p = 0.048; 71% vs 20%, p = 0.003). In both early and long UC duration, we did not find a correlation between inflammation or collagen deposition or MM thickness. There was a negative correlation between inflammation and aSMA positivity in the submucosa (R = 0.51, p = 0.003) and MM (R = 0.37, p = 0.04). Conclusions: In our series of colectomy specimens, there is more collagen deposition in UC than in controls. No association between disease duration and increased collagen deposition could be found. Expression of aSMA however is lower in UC and correlates with inflammation. Fibrosis in UC does not appear to increase significantly over time.

Background—Inflammatory processes seem to be involved in pulmonary arterial hypertension (PAH). CD40 ligand (L)may promote inflammation and thrombus formation, and we hypothesized that CD40L could be involved in thepathogenesis of PAH.Methods and Results—Several significant findings were revealed when examining the possible role of CD40L in PAH.(1) Patients with primary (n 13) and secondary (n 11) PAH but not those with chronic thromboembolic pulmonaryhypertension (n 8) had increased plasma levels of soluble (s) CD40L compared with control subjects (n 8). (2) PAHpatients using warfarin had markedly lower sCD40L levels than those without such therapy. (3) sCD40L levels werehigher in arterial (femoral artery) compared with mixed venous blood (pulmonary artery), suggesting enhanced releaseor reduced clearance in the pulmonary vasculature. (4) Platelets from PAH patients showed enhanced spontaneous andSFLLRN-stimulated release of sCD40L compared with control subjects. (5) In vitro, recombinant sCD40L inducedmonocyte chemoattractant protein (MCP)-1 and interleukin-8 gene expression in endothelial cells, and plasma levels ofthese chemokines were raised in all PAH groups, significantly correlated to sCD40L and hemodynamic parameters. (6)Although prostacyclin therapy (3 months) showed clinical benefit, this therapy had no effect on sCD40L and increasedMCP-1 levels in PAH patients, and prostacyclin enhanced MCP-1 in CD40L-stimulated endothelial cells.Conclusions—Our findings suggest a role for CD40L in the pathogenesis of PAH, possibly operating through aninteraction between platelets and endothelial cells involving chemokine-related mechanisms.(Circulation. 2004;110:999-1005.)Key Words: inflammation platelets hypertension, pulmonary endothelium

Inflammatory cytokines may negatively influence contractility and contribute to the remodelling process in the failing myocardium. Traditional cardiovascular drugs appear to have little influence on the overall cytokine network in chronic heart failure (CHF). Increased interest in anticytokine therapy has therefore evolved. Several small studies have used tumour necrosis factor (TNF)-α as a target, resulting in improved functional capacity and myocardial performance. Intravenous immunoglobulin (IVIG) represents another therapeutic approach in which the impact on myocardial performance appears to be correlated with anti-inflammatory effects. These studies demonstrate potential for immunomodulation as a therapy in addition to conventional cardiovascular treatment in CHF, but the most effective drugs in this regard have yet to be identified.

Summary Mannose-binding lectin (MBL) deficiency is associated with increased susceptibility to airways infections and autoimmunity. We examined whether MBL deficiency was more common in COPD patients, and whether MBL deficiency was associated with COPD severity. 415 COPD patients and 231 healthy subjects, aged 40–75, were examined in 2006/07. Plasma MBL levels were determined by ELISA. Low or deficient MBL levels were defined as plasma levels below 500 ng/mL or 100 ng/mL respectively. Logistic regression models determined factors associated with MBL deficiency; with explanatory variables study category, sex, age, smoking, comorbid heart disease, and CRP. For COPD severity, explanatory variables were FEV1, exacerbation history, hypoxia, respiratory symptoms, inhaled steroids, and CRP. 18.2% of healthy subjects and 22.2% of patients had MBL levels below 100 ng/mL (p = 0.23); 42.9% of healthy subjects and 49.6% of patients had levels below 500 ng/mL (p = 0.10). After adjustment for co-variables, patients had an OR (95% CI) of 1.26 (0.7, 2.2) for having MBL levels below 100 ng/mL compared with healthy subjects, and an OR (95% CI) of 1.06 (0.7, 1.7) for having levels below 500 ng/mL. Among the COPD patients, none of the disease variables were associated with MBL deficiency. No association was found between MBL deficiency and COPD or COPD severity.

OBJECTIVES We sought to study the gene expression of chemokines and their corresponding receptors in mononuclear blood cells (MNCs) from patients with chronic heart failure (CHF), both of which were cross-sectional and longitudinal studies during therapy with intravenous immunoglobulin (IVIg). BACKGROUND We have recently demonstrated that IVIg improves left ventricular ejection fraction (LVEF) in patients with CHF. Based on the potential pathogenic role of chemokines in CHF, we hypothesized that the beneficial effect of IVIg may be related to a modulatory effect on the expression of chemokines and their receptors in MNCs. METHODS We examined: 1) the gene expression of C, CC and CXC chemokines and their receptors in MNCs from 20 patients with CHF and 10 healthy blood donors; and 2) the expression of these genes in MNCs from 20 patients with CHF randomized in a double-blind fashion to therapy with IVIg or placebo for 26 weeks. RESULTS Our main findings in CHF were: 1) markedly raised gene expression of macrophage inflammatory protein (MIP)-1α, MIP-1β and interleukin (IL)-8; 2) enhanced gene expression of their corresponding receptors; 3) modulation in a normal direction of this abnormal chemokine and chemokine receptor gene expression during IVIg, but not during placebo therapy; 4) down-regulation of MIP-1α, MIP-1β and IL-8 during IVIg at the protein level in plasma; and 5) a correlation between down-regulation of MIP-1α gene expression and improved LVEF during IVIg therapy. CONCLUSIONS Our results further support a pathogenic role for chemokines in CHF and suggest that IVIg may represent a novel therapeutic approach, with the potential to improve LVEF in patients with CHF, possibly by modulatory effects on the chemokine network.

Previous studies suggest a relationship between systemic inflammation and body composition in chronic obstructive pulmonary disease (COPD). We examined the relationships between body composition (fat free mass index (FFMI) kg·m(-2) and fat mass index (FMI) kg·m(-2)) and three plasma inflammatory markers C-reactive Protein (CRP), soluble tumour necrosis factor receptor 1 (sTNF-R1) and osteoprotegerin (OPG) in 409 stable COPD patients (aged 40-75 yrs, Global Initiative for Obstructive Chronic Lung Disease (GOLD) categories II-IV, 249 male) from the Bergen COPD Cohort Study in Norway. FFMI and FMI were measured by bioelectrical impedance. Plasma CRP (μg·mL(-1)), sTNF-R1 (pg·mL(-1)) and OPG (ng·mL(-1)) were determined by enzyme immunoassays. Correlations and Kruskal-Wallis tests were used for bivariate analyses. Linear regression models were fitted for each of the three markers, CRP, sTNF-R1 and OPG, with FFMI and FMI as explanatory variables including sex, age, smoking habits, GOLD category, hypoxaemia, Charlson Comorbidity Index and inhaled steroid use as potential confounders. CRP and sTNF-R1 levels correlated positively with both FFMI and FMI. The adjusted regression coefficients for an increase in logCRP per unit increase in FFMI was 1.23 (1.14-1.33) kg·m(-2) and 24.9 (11.8-38.1) kg·m(-2) for sTNF-R1. Higher FMI was associated with a lower OPG, with adjusted regression coefficient -0.14 (-0.23- -0.04), whereas FFMI was unrelated to OPG. In conclusion, COPD patients with low FFMI had lower not higher plasma levels of CRP and sTNF-R1, whereas higher fat mass was associated with higher CRP and sTNF-R1 and lower OPG.

Background: Radiation therapy (RT) results in pain relief for about 6 of 10 patients with cancer induced bone pain (CIBP) caused by bone metastases. The high number of non-responders, the long median time from RT to pain response and the risk of adverse effects, makes it important to determine predictors of treatment response. Clinical features such as cancer type, performance status and pain intensity, and biomarkers for osteoclast activity are proposed as predictors of response to RT. However, results are inconsistent and there is a need for better predictors of RT response. A similar argument can be stated for the development of cachexia; there are currently no predictors that can identify patients who will develop cachexia later in the cancer disease trajectory. Experimental and preclinical studies show that pain, depression and cachexia are related to inflammation. However, it is not known if inflammatory biomarkers can predict CIBP, depression or development of cachexia. Methods: This multicenter, multinational longitudinal observational study will include 600 adult patients receiving RT for CIBP. Demographic data, clinical variables, osteoclast and inflammatory biomarkers will be assessed before start of RT, and 3, 8, 16, 24 and 52 weeks after last course of RT. The primary aim of the study is to identify potential predictors for pain relief from RT. Secondary aims are to explore potential predictors for development of cachexia, the longitudinal relationship between pain intensity and depression, and if inflammatory biomarkers are associated with changes in pain intensity, cachexia and depression during one-year follow up. Discussion: The immediate clinical implication of the PRAIS study is to identify potential predictive factors for a RT response on CIBP, and thereby reduce non-efficacious RT. Patient benefits are fewer hospital visits, reduced risk of adverse effects and more individualized pain treatment. The long-term clinical implication of the PRAIS study is to improve the knowledge about inflammation in relation to CIBP, cachexia and depression and potentially identify associations and mechanisms that can be targeted for treatment. Trial registration: ClinicalTrials.gov NCT02107664 , date of registration April 8, 2014 (retrospectively registered). Trial sponsor: The European Palliative Care Research Centre (PRC), Department of Clinical and Molecular Medicine, NTNU, Faculty of medicine and Health Sciences, Trondheim, N-7491, Norway. The Palliative Radiotherapy and Inflammation Study (PRAIS) is funded by a non-restricted grant given by the Norwegian Cancer Society (NCS) to the European Palliative Care Research Centre (PRC). In addition, the study has financing for a PhD scholarship from the Liaison Committee for Education, Research and Innovation in Central Norway. The study sponsors and funders are not involved in data collection, analyses, interpretation or publication of data