Serum Concentrations Of TNF-alpha Research Articles

Endotoxin and Plasminogen Activator Inhibitor‐1 Serum Levels Associated With Nonalcoholic Steatohepatitis in Children

Recent evidence supports a role for endotoxemia in the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH). We investigated the association between serum levels of endotoxin, proinflammatory molecules, and histology in children with NAFLD. A total of 40 children, mean age of 11.9 +/- 2.8 years (27 male and 13 female), with biopsy-proven NAFLD were consecutively enrolled. Anthropometrics, blood pressure, and parameters of the metabolic syndrome were collected. Serum levels of endotoxin, plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 were measured by an enzyme-linked immunosorbent assay and compared with circulating levels of the same soluble factors in 9 age- and sex-matched normal weight controls (age 11.4 +/- 1.7 years; 6 boys and 3 girls). Children with NAFLD had markedly higher serum concentrations of endotoxin (P < 0.01), PAI-1 (P < 0.001), TNF-alpha, and IL-6 (P < 0.05) than control subjects. Endotoxin (P = 0.002), PAI-1, (P < 0.001), IL-6 (P = 0.002), TNF-alpha (P = 0.02), and body mass index (P = 0.03) were significantly associated with a NAFLD activity score >or=5 at the univariate analysis. At the stepwise regression analysis, endotoxin (P < 0.0001) and PAI-1 (P = 0.009) were the most significant predictors for NAFLD activity score. Our findings demonstrate that, apart from TNF-alpha and IL-6, endotoxin and PAI-1 may represent good markers of NASH. They also reinforce the hypothesis that elevated levels of endotoxin may contribute to the progression from NAFLD to NASH.

Serum Concentrations of TNF α and Its Soluble Receptors in Patients with Adrenal Tumors Treated by Surgery

The peripheral blood levels of TNF α and its soluble receptors were studied in 39 patients with malignant and benign adrenal tumors treated by adrenalectomy. The concentrations of TNF α were significantly elevated in patients with malignant tumors of the adrenal cortex and in patients with Conn’s syndrome compared to control. In patients with non-functioning adenomas and pheochromocytomas, TNF α levels were similar to those detected in the control. In subjects with myelolipomas, the serum concentration of TNF α was lower compared to the control. After adrenalectomy, the levels of TNF α were decreased in patients with malignant tumors and in patients with Conn’s syndrome, nonfunctioniong adenomas and pheochromocytomas compared to the concentration before surgery. The serum concentrations of soluble receptors of TNF α did not differ among different patient groups and compared to the control. After adrenalectomy, the blood concentrations of TNF α R1 and TNF α R2 were decreased in patients with Conn’s syndrome. However, to confirm practicality of the evaluation of TNF α and its soluble receptors in differential diagnosis in patients with adrenal tumors, a larger study group is needed.

Oat Bran Reduces Serum Level Of Tumor Necrosis Factor - Alpha In Sedentary And Trained Rats

Acute physical exercise is known to induce a pro-inflammatory cytokine profile in the plasma. On the other hand, studies have shown that exercise training induces decreased cytokine secretion by skeletal muscle and lymphocytes. Oat-containing diets are related with diminished plasma levels of inflammatory markers; however, the effect of this supplementation on exercise-induced inflammation is controversial. PURPOSE: To analyze the effects of oat bran intake on TNF-alpha serum concentration in sedentary and trained rats. METHODS: Male Wistar rats were divided into four experimental groups: sedentary (S), sedentary receiving oat bran (SO), trained (T) and trained receiving oat bran (TO). Experimental chow was prepared from a commercial chow, which was added 30% of oat bran. Training protocol consisted in 60 minutes daily swimming, five days/ week, for eight weeks. TNF-alpha serum level was carried out by ELISA. RESULTS: TNF-alpha serum level was decreased in T (3.1-fold, p<0.05) and SO (50%, p<0.05), when compared to S. Moreover, TO showed TNF-alpha concentration minor than T (1.9-fold, p<0.05). CONCLUSION: These data show that oat bran intake induces a reduction in TNF-alpha serum level both in sedentary and trained rats, showing a modulatory effect of oat bran on the profile of this cytokine. Furthermore, the association of oat bran intake and exercise was able to induce a synergic role in reducing TNF-alpha concentration. We conclude that oat bran has a potential anti-inflammatory effect and it is able to potentiate the training-induced anti-inflammatory effect.

Modulation of Brain Dead Induced Inflammation by Vagus Nerve Stimulation

Because the vagus nerve is implicated in control of inflammation, we investigated if brain death (BD) causes impairment of the parasympathetic nervous system, thereby contributing to inflammation. BD was induced in rats. Anaesthetised ventilated rats (NBD) served as control. Heart rate variability (HRV) was assessed by ECG. The vagus nerve was electrically stimulated (BD + STIM) during BD. Intestine, kidney, heart and liver were recovered after 6 hours. Affymetrix chip-analysis was performed on intestinal RNA. Quantitative PCR was performed on all organs. Serum was collected to assess TNFalpha concentrations. Renal transplantations were performed to address the influence of vagus nerve stimulation on graft outcome. HRV was significantly lower in BD animals. Vagus nerve stimulation inhibited the increase in serum TNFalpha concentrations and resulted in down-regulation of a multiplicity of pro-inflammatory genes in intestinal tissue. In renal tissue vagal stimulation significantly decreased the expression of E-selectin, IL1beta and ITGA6. Renal function was significantly better in recipients that received a graft from a BD + STIM donor. Our study demonstrates impairment of the parasympathetic nervous system during BD and inhibition of serum TNFalpha through vagal stimulation. Vagus nerve stimulation variably affected gene expression in donor organs and improved renal function in recipients.

Tumor necrosis factor alpha and its soluble receptors in obese children with NAFLD

To evaluate the serum levels of tumor necrosis factor (TNF) alpha and its soluble receptors in obese children with non-alcoholic fatty liver disease (NAFLD). Fasting serum levels of TNFalpha and its receptors were determined in 45 consecutive obese children with suspected liver disease and 20 lean controls. The degree of liver steatosis was graded in ultrasound according to Saverymuttu. 1H-MR spectroscopy was performed with 1.5T scanner with PRESS sequence. A fatty liver was confrmed in 32 children by ultrasonography (group I); 16 of them also had increased ALT activity (group Ia - NAFLD). Serum concentrations of TNFalpha and its receptors were significantly higher in obese children with NAFLD compared to controls. Significant correlation was found between ultrasonographic grade of liver steatosis and TNFalpha level but serum level of this adipokine was not significantly different in children with advanced liver steatosis (grade 2-3, n=13) compared to patients with mild steatosis (grade 1, n=19). The ability of TNFalpha and its receptors (R1, R2) to differentiate children with advanced liver steatosis from those with mild steatosis was insignificant. However, the ability of serum TNFalpha to differentiate obese children with liver steatosis from those without steatosis was significant (AUC=0.7448, p=0.0291). Although TNFalpha does not predict advanced liver steatosis, it may be suitable serum marker in predicting liver steatosis in obese children.

Anti-Inflammatory Effect of Guan-Xin-Er-Hao via the Nuclear Factor-Kappa B Signaling Pathway in Rats with Acute Myocardial Infarction

A traditional Chinese medicine, Guan-Xin-Er-Hao (GXEH), is a famous multiple target therapeutic polypharmaceutical. Our aim was to evaluate whether or not oral administration of GXEH has an anti-inflammatory effect associated with blockade of nuclear factor-kappa B (NF-kappaB), and to investigate the NF-kappaB-mediated pro-inflammatory cytokines expression pathway during acute myocardial infarction (AMI) in rats. Sprague-Dawley rats were randomly assigned to four groups: oral GXEH administered at 15 or 5 g/kg, the vehicle control and sham-operated groups. Thirty minutes after giving GXEH or 0.9% NaCl (p.o.) once, coronary arteries were occluded except for the sham-operated rats. We measured 24-h infarct size, 3-h expression of NF-kappaB protein in the myocardial left ventricular tissues and serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and C-reactive protein (CRP). Compared with rats receiving vehicle, rats administered 15 g/kg GXEH had significantly reduced 24-h infarct size, expression of NF-kappaB protein and serum concentrations of TNF-alpha, IL-6, and CRP. GXEH at 5 g/kg did not have a significant effect on these parameters. In conclusion, GXEH exhibited an anti-inflammatory effect through inhibition of the NF-kappaB-mediated signaling pathway leading to downregulation of pro-inflammatory cytokine expression. These findings provide new evidence of the cardioprotective effect of GXEH through reduction of infarct size by mediating lots of endogenous materials via multiple pathways to act on myocardial cells in the treatment of cardiovascular disease.

The impact of shift work induced chronic circadian disruption on IL-6 and TNF-α immune responses

AIMSleep disturbances induce proinflammatory immune responses, which might increase cardiovascular disease risk. So far the effects of acute sleep deprivation and chronic sleep illnesses on the immune system have been investigated. The particular impact of shift work induced chronic circadian disruption on specific immune responses has not been addressed so far.MethodsPittsburgh-Sleep-Quality-Index (PSQI) questionnaire and blood sampling was performed by 225 shift workers and 137 daytime workers. As possible markers the proinflammatory cytokines IL-6 and TNF-α and lymphocyte cell count were investigated. A medical examination was performed and biometrical data including age, gender, height, weight, waist and hip circumference and smoking habits were collected by a structured interview.ResultsShift workers had a significantly higher mean PSQI score than day workers (6.73 vs. 4.66; p < 0.001). Day workers and shift workers had similar serum levels of IL-6 (2.30 vs. 2.67 resp.; p = 0.276), TNF-α (5.58 vs. 5.68, resp.; p = 0.841) or lymphocytes count (33.68 vs. 32.99, resp.; p = 0.404). Furthermore there were no differences in cytokine levels (IL-6 p = 0.761; TNF-α p = 0.759) or lymphocyte count (p = 0.593) comparing the sleep quality within the cohorts. When this calculation of sleep quality was stratified by shift and day workers irrespective of their sleep quality day workers and shift workers had similar serum levels of IL-6, TNF-α or lymphocytes count. Multiple linear regression analysis showed a significant correlation of lymphocytes count and smoking habits.ConclusionShift work induces chronic sleep debt. Our data reveals that chronic sleep debt might not always lead to an activation of the immune system, as we did not observe differences in lymphocyte count or level of IL-6 or TNF-α serum concentration between shift workers and day workers. Therefore chronic sleep restriction might be eased by a long-term compensating immune regulation which (in healthy) protects against an overstimulation of proinflammatory immune mechanisms and moderates metabolic changes, as they are known from short-term sleep deprivation or sleep related breathing disorders.

Lung inflammation and endothelial cell damage are decreased after treatment with phototherapy (PhT) in a model of acute lung injury induced by Escherichia coli lipopolysaccharide in the rat

Lipopolysaccharide (LPS) mimics the symptoms of acute lung injury (ALI), which is characterized by the accumulation in the lungs of neutrophils producing inflammatory mediators. Because of the lack of information about phototherapy (PhT) effects on ALI, we investigated whether PhT (685nm InGaAlP) attenuates LPS-induced ALI. PhT reduced lung edema, the accumulation of TNF-alpha in the lung, and myeloperoxidase (MPO) activity. However, PhT was not efficient in reducing of TNF-alpha concentration in both serum and neutrophils of blood after LPS. In another series of experiments, in vitro assays of the effects of PhT effect on mouse pulmonary arterial endothelium cells (MPAECs) after TNF-alpha showed that the laser restores the MPAECs damage induced at 6 or 24h after TNF-alpha. These results suggest the PhT effect on ALI is partly due to inhibition of TNF-alpha release from neutrophils and lung cells.

Inflammatory mediators and premature coronary atherosclerosis in rheumatoid arthritis

Rheumatoid arthritis (RA) is an inflammatory disease associated with premature atherosclerosis. We hypothesized that mediators of inflammation associated with atherosclerosis in other populations (interleukin-6 [IL-6], tumor necrosis factor alpha [TNFalpha], serum amyloid A [SAA], vascular endothelial growth factor, neutrophil count, IL-1alpha, E-selectin, intercellular adhesion molecule 1 [ICAM-1], myeloperoxidase [MPO], matrix metalloproteinase 9, and vascular cell adhesion molecule 1) would be increased and associated with the severity of coronary atherosclerosis in patients with RA. Clinical variables, concentrations of inflammatory mediators, and coronary artery calcification were measured in 169 patients with RA and 92 control subjects. Differences in concentrations of inflammatory mediators were compared using median quantile regression. The relationship of inflammatory mediators with the severity of coronary calcification in RA and control subjects was examined using proportional odds logistic regression, allowing for interaction with disease status. Models were adjusted for traditional cardiovascular risk factors. Median serum concentrations of IL-6, SAA, ICAM-1, E-selectin, TNFalpha, and MPO and peripheral blood neutrophil count were higher in patients with RA than controls (all P < 0.05), independent of Framingham risk score and diabetes mellitus (DM). IL-6 (main effect odds ratio [OR] 1.72; 95% confidence interval [95% CI] 1.12, 2.66) and TNFalpha (main effect OR 1.49; 95% CI 1.16, 1.90) concentrations were significantly associated with higher amounts of coronary calcium, independent of Framingham risk score and DM, and such main effects significantly differed from controls (P = 0.001 and 0.03 for interaction, respectively). TNFalpha and IL-6 are significantly associated with the severity of subclinical atherosclerosis, independent of Framingham risk score, in RA.

Limb Ischemic Preconditioning Reduces Heart and Lung Injury After an Open Heart Operation in Infants

Open heart surgery supported by cardiopulmonary bypass is associated with heart and lung ischemia-reperfusion injury (IRI). Limb remote ischemic preconditioning (RIPC) reduces injury caused by ischemia-reperfusion in multiple distant organs. We conducted a prospective clinical trial (randomized and controlled) to test the feasibility and safety of limb RIPC, as well as its protective effects against myocardial and pulmonary IRI for infants undergoing repair of simple congenital heart defects. Infants undergoing repair of ventricular septal defects were enrolled in our study and randomly assigned to one of two treatment groups: limb RIPC or control. RIPC was induced twice (24 h and 1 h preoperatively) via three 5-min cycles of ischemia and reperfusion on the left upper arm using a blood pressure cuff. Lung compliance, respiratory index (RI), and cardiac inotropic score (IS) were calculated for each patient. Serum concentrations of the following factors were measured perioperatively: interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor (TNF)-alpha; lactate dehydrogenase (LDH), creatine kinase (CK), and its isoenzyme (CK-MB), and troponin I (TnI); malondialdehyde (MDA) and superoxide dismutase (SOD). The expression of heat shock protein 70 (HSP 70) in cardiomyocytes was analyzed by Western blot. Surgical outcomes, including limb movement and sensory function, were recorded in detail. Sixty infants weighting less than 7 kg were studied, with 30 patients in the RIPC group and 30 in the control group. Within 6 months of discharge from the hospital, no limb disability, sensory disturbance, or other surgical complications were found in any patient. Compared with the control group, patients in the RIPC group had higher Cs and Cd, along with lower RI and IS at various postoperative phases. At the beginning of the operation, serum concentrations of IL-6, IL-8, IL-10, TNF-alpha, LDH, CK, and TnI were higher in the RIPC group than the control group. Postoperatively, release of cytokines and leakage of heart enzymes were attenuated in the RIPC group; serum concentrations of cytokines and heart enzymes were lower in the RIPC group at some, but not all, postoperative time points. Furthermore, the RIPC group had lower coronary sinus venous concentrations of MDA and higher concentrations of SOD. Similarly, the expression of HSP 70 was upregulated in cardiomyocytes from the RIPC group. Limb RIPC can be applied safely and easily in infants, can attenuate systemic inflammatory response syndrome, and can increase systemic tolerance to IRI, imparting a protective effect against myocardial and pulmonary IRI. The expression of HSP 70 has an important role in the mechanism of action for RIPC.

Effect of Training Judo in the Competition Period on the Plasmatic Levels of Leptin and Pro-inflammatory Cytokines in High-Performance Male Athletes

The purpose this study was to evaluate the effect of training judo in the competition period on the plasmatic levels of bioactive molecules in high-performance male athletes. The subjects were divided into two groups, a trained group with 11 judokas and a nontrained group also with 11 subjects. Blood samples obtained 60 h after training to measure plasma tumor necrosis factor (TNF-alpha), interleukin-6 (IL-6), monocyte chemotactic protein 1 (MCP-1), and leptin levels. The trained group presented a significant reduction in the percentage of fat and fat mass and an increase in the lumbar and lower limbs traction forces and the maximum VO(2) when compared to the nontrained group. There was no significant difference in the serum concentrations of TNF-alpha and IL-6 between the two groups. The trained group presented a lower concentration of leptin, both as absolute values as well as relative to the percentage of fat, and a higher concentration of MCP-1, in relation to the nontrained group. Our results suggest an adaptation in the capacity of synthesizing and secreting leptin in response to chronic stress in judo, what suggests a neuro-hormonal adjustment that guarantees the efficiency of metabolism. The changes of MCP-1 indicated a possible inflammatory state.

High sensitivity cytokine detection in acute coronary syndrome reveals up-regulation of Interferon Gamma and Interleukin-10 post Myocardial Infarction

Inflammation is an important element in the development and destabilization of atherosclerotic plaque. Using a high sensitivity multiplex assay, previously untested in the context of atherosclerotic disease, we determined serum concentrations of GM-CSF, IFNgamma, IL-1beta, IL-2, IL-10, IL-12p70, TNF alpha, IL-6, and IL-8 in 48 Myocardial Infarction (MI) patients, 14 Unstable Angina (UA) patients and 12 healthy controls. IFNgamma levels were significantly higher in MI compared to UA (p=0.0091) and Control groups (p=0.0014). IL-10 also showed higher expression levels between MI, UA groups and Controls (p=0.0299).This up-regulation may reflect the extent of plaque instability and/or rupture in MI patients.Our observations provide evidence that IFNgamma and IL-10 merit further investigation in atherosclerotic disease states as potential markers of disease and therapeutic targets.

ANGIOTENSIN‐CONVERTING ENZYME INHIBITORS IMPROVE HEPATIC STEATOSIS BY MODULATING EXPRESSION OF TUMOUR NECROSIS FACTOR‐α, INTERLEUKIN‐6 AND ADIPONECTIN RECEPTOR‐2 IN RATS WITH TYPE 2 DIABETES

1. Angiotensin-converting enzyme inhibitors (ACEI) are hypotensive drugs that have been shown to prevent Type 2 diabetes mellitus (T2DM) in high-risk individuals. However, in T2DM, the effects of ACEI on hepatic steatosis are not known. The aim of the present study was to examine the effects of ACEI on changes in liver histology and hepatic mRNA expression of adipokines in rats with T2DM. 2. Thirty-six rats were divided into a normal control group, a T2DM group and a fosinopril-treated group. After six weeks of treatment with 5 mg/kg per day fosinopril, an ACEI, changes in liver histology, serum fasting glucose (FG), insulin, triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, adiponectin were evaluated, as was hepatic TNF-alpha, IL-6 and adiponectin receptor-2 (adipoR2) mRNA expression. 3. The degree of hepatic steatosis and inflammation, serum FG, insulin, TG, TC, ALT, TNF-alpha and IL-6 concentrations and hepatic TNF-alpha and IL-6 mRNA expression were significantly higher in rats with T2DM than in normal controls. Serum adiponectin concentrations and hepatic adipoR2 mRNA expression in rats with T2DM were significantly lower than in normal controls. Fosinopril significantly reduced the degree of hepatic steatosis, serum FG, insulin, ALT, TNF-alpha and IL-6 concentrations and hepatic TNF-alpha and IL-6 mRNA expression. Fosinopril significantly increased serum adiponectin concentrations and hepatic adipoR2 mRNA expression. 4. In conclusion, the ACEI improved insulin sensitivity and hepatic steatosis in rats with T2DM by increasing circulating adiponectin and hepatic adipoR2 levels, in addition to reducing pro-inflammatory cytokine levels in the circulation and liver.

The IGF system and cytokine interactions and relationships with longitudinal growth in prepubertal patients with cystic fibrosis

Growth delay is a feature of patients with cystic fibrosis (CF). CF is a condition characterized by chronic inflammation that has been shown to modify the IGF system, which is essential for normal growth, and is related to pulmonary function in CF patients. We aimed to verify whether circulating levels of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, insulin and the IGF system were related and/or had relationships with linear growth in children with CF. Seventeen prepubertal CF patients (nine males and eight females) in a stable clinical condition were enrolled. Auxological parameters, pulmonary function and the Shwachman-Kulczycki (S-K) score were assessed, and serum samples were drawn at baseline and after 12 months. TNF-alpha, IL-6, IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3 and insulin were assayed using specific commercial kits. At baseline, TNF-alpha serum concentration was related to serum IGF-I concentration (R = 0.53), IGF-II bioactivity (IGF-II/IGFBP-3 molar ratio, R = +0.52) and insulin concentration (R = +0.63). Changes in serum IL-6 and IGFBP-2 concentrations during the 12-month observation were positively correlated (R = +0.63). Changes in height standard deviation score (Ht SDS) were correlated with IGF-I serum concentrations at baseline (R =+0.67) and after 12 months (R = +0.70), with IGF-I bioavailability and with IGFBP-1 serum concentrations (R = -0.88). Body mass index (BMI) SDS correlated with IGF bioavailability. This study showed a relationship between inflammatory status and the IGF system, and an effect of these interactions on longitudinal growth. Moreover, a role for insulin in growth was identified. Better control of inflammation and preservation of insulin secretion could benefit these patients.

Anti‐inflammatory Effect of Palmitoylethanolamide on Human Adipocytes

Obesity leads to the appearance of an inflammatory process, which can be initiated even with a moderate weight gain. Palmitoylethanolamide (PEA) is an endogenous lipid, secreted by human adipocytes, that possesses numerous anti-inflammatory properties. The main purpose of this study was to investigate the anti-inflammatory effect of PEA on human adipocytes, as well as in a murine model. The production of tumor necrosis factor-alpha (TNF-alpha) by lipopolysaccharide (LPS)-treated human subcutaneous adipocytes in primary culture and CF-1 mice was investigated by enzyme-linked immunosorbent assay. The effects of PEA on adipocyte TNF-alpha secretion were explored as well as some suspected PEA anti-inflammatory pathways: nuclear factor-kappaB (NF-kappaB) pathway, peroxisome proliferator-activated receptor-alpha (PPAR-alpha) gene expression, and TNF-alpha-converting enzyme (TACE) activity. The effects of PEA on the TNF-alpha serum concentration in intraperitoneally LPS-treated mice were also studied. We demonstrate that the LPS induced secretion of TNF-alpha by human adipocytes is inhibited by PEA. This action is neither linked to a reduction in TNF-alpha gene transcription nor to the inhibition of TACE activity. Moreover, PPAR-alpha is not implicated in this anti-inflammatory activity. Lastly, PEA exhibits a wide-reaching anti-inflammatory action as the molecule is able to completely inhibit the strong increase in TNF-alpha levels in the serum of mice treated with high doses of LPS. In view of its virtual lack of toxicity, PEA might become a potentially interesting candidate molecule in the prevention of obesity-associated insulin resistance.

Tetrandrine Increased the Survival Rate of Mice With Lipopolysaccharide-Induced Endotoxemia

Endotoxemia usually causes significant morbidity and mortality, and treatment of endotoxemia is often ineffective. The effects of tetrandrine (a bisbenzylisoquinoline alkaloid) on lipopolysaccharide (LPS)-induced endotoxemia were investigated in mice. The peritoneal macrophages were stimulated with LPS and treated with or without tetrandrine. The amounts of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-10 secreted by peritoneal macrophages were measured by enzyme-linked immunosorbent assay. Mice were intraperitoneally injected with LPS to induce endotoxemia and were treated or not treated with oral gavage with 150 mg/kg tetrandrine 1 hour before or after LPS injection. The survival rate of the mice was determined after they were treated with various regiments. The amounts of TNF-alpha, IL-1beta, IL-6, and IL-10 in the serum of the mice were measured by enzyme-linked immunosorbent assay, and the high mobility group box 1 (HMGB1) concentration was studied by Western blot analysis. Tetrandrine suppressed the LPS-induced increase of TNF-alpha, IL-1beta, and HMGB1 secretion by peritoneal macrophages but did not affect the IL-6 and IL-10 concentrations. The animals treated with tetrandrine either 1 hour before or after LPS injection had a 100% survival rate, which was significantly higher than that of the control group (40%) (p = 0.005). The LPS-induced increase in serum TNF-alpha, IL-1beta, and HMGB1 concentrations was reduced by tetrandrine treatment administered either 1 hour before or after LPS injection (p < 0.0001). In contrast, tetrandrine prolonged the LPS-induced elevation in serum IL-10 concentrations only mildly changed the serum IL-6 concentrations. Tetrandrine treatment either 1 hour before or 1 hour after LPS injection reduced the mortality rate of the mice with LPS-induced endotoxemia. The effects of tetrandrine on LPS-induced endotoxemia might be related to the suppression of TNF-alpha, IL-1beta, and HMGB1 concentrations.

IL-10 administration attenuates pulmonary neutrophil infiltration and alters pulmonary iNOS activation following hemorrhagic shock

Several studies report immuno-modulatory effects of endogenous IL-10 after trauma. This study investigates the effect of IL-10 administration on systemic and pulmonary inflammation in hemorrhagic shock. Male C57/BL6 mice (4-6 animals per group) were subjected to volume controlled hemorrhagic shock for 3 hrs followed by resuscitation. Animals were either subcutaneously injected with 0.9 % saline (Shock group) or with recombinant mouse IL-10 (Shock+IL-10 group) 1 h before and 1 h after the induction of hemorrhagic shock. Serum TNF-alpha, IL-6, and keratinocyte (KC) concentrations were measured with the Luminex multiplexing platform. Acute pulmonary inflammation was assessed by pulmonary myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activity. IL-10 administration significantly decreased serum TNF-alpha (10.30 +/- 1.68 vs 37.42 +/- 10.64; p < 0.05), IL-6 (44.22 +/- 6.65 vs 85.24 +/- 7.94; p < 0.05), and KC (276.74 +/- 52.67 vs 465.61 +/- 58.98; p < 0.05) levels following hemorrhagic shock. Further, pulmonary MPO activity was significantly lower (2698.85 +/- 431.10 vs 4580.67 +/- 294.38; p < 0.05) and pulmonary iNOS activity upregulated. These findings suggest that administration of IL-10 modulates the degree of hemorrhage-induced systemic and pulmonary inflammation and support the notion of a central role for iNOS in acute lung injury.

Tumor Necrosis Factor-α −308 Genotypes Influence Inflammatory Activity and TNF-α Serum Concentrations in Children with Juvenile Idiopathic Arthritis

Considering the relevance of tumor necrosis factor-alpha (TNF-alpha) in the pathophysiology of juvenile idiopathic arthritis (JIA), it is likely that polymorphisms in its promoter area may be relevant in disease susceptibility and activity. We investigated if clinical measures of JIA activity and TNF-alpha serum concentrations were associated with TNF-alpha -308 genotypes. Portuguese patients with JIA in 5 pediatric rheumatology centers were recruited consecutively, along with a control group of healthy subjects. Demographic and clinical data and blood samples were collected from each patient. DNA was extracted for analysis of TNF-alpha gene promoter polymorphisms at position -308 by restriction fragment-length polymorphism. One hundred fourteen patients and 117 controls were evaluated; 57% of patients presented the oligoarticular subtype, 25% the polyarticular subtype, 8% the systemic subtype, and 9% had enthesitis-related arthritis and 5% psoriatic arthritis. Twenty-four percent of the patients presented the -308 GA/AA genotypes and 76% the -308 GG genotype, similar to findings in controls. Patients with the -308 GA/AA genotype had higher degree of functional impairment, erythrocyte sedimentation rate, 100-mm visual analog scale score for disease activity, and TNF-alpha levels compared to those with the -308 GG genotype. TNF-alpha -308 GA/AA genotypes were found to be related to higher inflammatory activity and worse measures of disease activity in Portuguese patients with JIA. They were not associated with susceptibility to JIA.

Establishment of a cut‐point value of serum TNF‐α levels in the metabolic syndrome

Cardiovascular diseases and type 2 diabetes are the major causes of mortality in Mexico. Metabolic syndrome (MS) is a cluster of factors that increase the risk to develop such diseases. Previous studies have shown that MS is associated with high tumor necrosis factor (TNF-alpha) levels. In fact, TNF-alpha has been proposed to be a useful marker for clinical diagnosis of inflammation at an early stage. Therefore, we analyzed TNF-alpha concentrations in Mexican individuals with or without MS and related these levels to the associated MS components. Clinical, anthropometric, and biochemical data were analyzed in 41 healthy and 39 MS individuals. Individuals were similarly grouped by age and gender.The serum TNF-alpha levels measured by a highly sensitive enzyme-linked immunosorbent assay (ELISA) kit were increased significantly in MS subjects compared with healthy individuals (P<0.001). The assay showed 78.1% sensitivity and 61.5% specificity with a cut-point level of 1.36 pg/mL. TNF-alpha levels higher than the cut-point value were correlated with insulin resistance indices. These findings support the hypothesis that serum TNF-alpha concentration could be a useful marker for early MS diagnosis. Nevertheless, we suggest the establishment of specific cut-point values in each studied population to evaluate potential clinical applications.

Thoracic epidural anesthesia reverses sepsis-induced hepatic hyperperfusion and reduces leukocyte adhesion in septic rats

IntroductionLiver dysfunction is a common feature of severe sepsis and is associated with a poor outcome. Both liver perfusion and hepatic inflammatory response in sepsis might be affected by sympathetic nerve activity. However, the effects of thoracic epidural anesthesia (TEA), which is associated with regional sympathetic block, on septic liver injury are unknown. Therefore, we investigated hepatic microcirculation and inflammatory response during TEA in septic rats.MethodsForty-five male Sprague-Dawley-rats were instrumented with thoracic epidural catheters and randomized to receive a sham procedure (Sham), cecal ligation and puncture (CLP) without epidural anesthesia (Sepsis) and CLP with epidural infusion of 15 ul/h bupivacaine 0.5% (Sepsis + TEA). All animals received 2 ml/100 g/h NaCl 0.9%. In 24 (n = 8 in each group) rats, sinusoidal diameter, loss of sinusoidal perfusion and sinusoidal blood flow as well as temporary and permanent leukocyte adhesion to sinusoidal and venolar endothelium were recorded by intravital microscopy after 24 hours. In 21 (n = 7 in each group) separate rats, cardiac output was measured by thermodilution. Blood pressure, heart rate, serum transaminase activity, serum TNF-alpha concentration and histologic signs of tissue injury were recorded.ResultsWhereas cardiac output remained constant in all groups, sinusoidal blood flow increased in the Sepsis group and was normalized in rats subjected to sepsis and TEA. Sepsis-induced sinusoidal vasoconstriction was not ameliorated by TEA. In the Sepsis + TEA group, the increase in temporary venolar leukocyte adherence was blunted. In contrast to this, sinusoidal leukocyte adherence was not ameliorated in the Sepsis + TEA group. Sepsis-related release of TNF-alpha and liver tissue injury were not affected by Sepsis + TEA.ConclusionsThis study demonstrates that TEA reverses sepsis-induced alterations in hepatic perfusion and ameliorates hepatic leukocyte recruitment in sepsis.