Circulating Levels Of TNF-α Research Articles

Dynamics of enterocyte tight junctions: effect of experimental colitis and two different anti-TNF strategies

An alteration of the intestinal barrier is considered to represent an early step in pathogenesis of Crohn's disease. The integrity of intestinal barrier function is guaranteed among other factors by enterocyte tight junction (TJ) proteins. Clinical and experimental data indicate the TNF-alpha to be the major responsible factor for these defects. In the present study we investigated the very early effects of DNBS-ethanol colitis on ileal enterocyte TJ proteins [occludin, zonula occludens-1 (ZO-1), claudin-2] in controls, mice treated with infliximab (IFX) or with etanercept (ETC), and in knockout mice for the TNF-alpha receptor 1 (TNFR-1(-/-)). Circulating TNF-alpha levels were effectively reduced by IFX and ETC (P < 0.01, both) at 3 and at 6 h. DNBS colitis induced disappearance of occludin and ZO-1 from enterocyte cell-cell contact, whereas claudin-2, absent under control conditions, appeared in the ileal epithelium. These alterations were prevented equally by both treatments, IFX and ETC, and in TNFR-1(-/-) animals. DNBS colitis induced a very rapid loss of occludin and ZO-1 from ileal TJ together with an upregulation of claudin-2. Our data are consistent with the hypothesis that TNF-alpha is involved in early TJ rearrangement and that its effects are mediated through TNFR-1. Despite clinical differences, both anti-TNF treatments were equally effective in the present setting.

The effect of different preparations of hormone therapy on tumor necrosis factor-α levels in women with surgical menopause

The aim of the present prospective controlled study was to examine the influence of 17β-estradiol and tibolone on tumor necrosis factor-α (TNF-α) levels in healthy women with surgical menopause. Forty-five surgically menopausal women were included in the study. Thirty women were randomized to receive tibolone 2.5 mg or 17β-estradiol 2 mg daily for 16 weeks. Fifteen surgically menopausal women who refused hormone therapy served as controls. Serum was collected from the subjects at baseline and at the end of the study for TNF-α assay. Neither tibolone nor 17β-estradiol showed a significant influence on TNF-α level at the end of 16 weeks in comparison with baseline. Although tibolone induced a trend toward decreased level of TNF-α (3.30 ± 0.42 vs. 2.56 ± 1.94 μg/dl), this was non-significant. The slight increase observed in TNF-α level in the control group was also insignificant (3.60 ± 1.20 vs. 4.10 ± 0.70 μg/dl). Overall, these results demonstrate no significant effects of either tibolone or 17β-estradiol on circulating TNF-α level in surgically menopausal women. However, the significant difference achieved between the tibolone and control group after treatment is promising and needs to be investigated in trials with longer treatment periods.

TNF blockade aggravates experimental chronic Chagas disease cardiomyopathy

Chronic Chagas disease cardiomyopathy (CCC), caused by Trypanosoma cruzi, is an inflammatory dilated cardiomyopathy associated with increased circulating levels of TNF-α. We investigate whether TNF blockade with Etanercept during the chronic phase of T. cruzi infection could attenuate experimental CCC development. The effect of Etanercept was evaluated after 11 months of T. cruzi infection on survival, parasitism, left ventricular function, intensity of myocarditis, fibrosis, and left ventricular mRNA expression of cytokines and TNF-α-induced genes. Left ventricular function was significantly reduced in treated animals as compared to infected untreated animals. Blood and cardiac parasitism as well as survival rate were not altered with Etanercept treatment. Inflammatory infiltrates were located predominantly in the subendocardic region in treated animals, whereas in untreated animals inflammation was scattered throughout the myocardium. Left ventricular mRNA IL-10 expression was significantly higher, and iNOS, significantly lower in treated than in untreated animals. mRNA expression of TNF-α, IFN-γ, TGF-β, A20 and ANP was similar in both groups. Our results suggest that TNF-α/LT-α blockade with Etanercept enhances left ventricular dysfunction in T. cruzi-induced chronic cardiomyopathy and the absence of TNF signaling may be deleterious to the failing heart in Chagas disease cardiomyopathy.

Pretreatment of curcumin attenuates coagulopathy and renal injury in LPS-induced endotoxemia

Disseminated intravascular coagulation (DIC) is a lethal situation in severe infections, characterized by the systemic formation of microthrombi complicated with bleeding tendency and organ dysfunction. Current clinical trials are not promising. In this study, we investigated the protective effect of curcumin in a lipopolysaccharide (LPS)-induced DIC model in rats. Experimental DIC was induced by sustained infusion of LPS (10 mg/kg body weight) for 4 h through the tail vein. Curcumin (60 mg/kg body weight) was given intraperitoneally 3 h before LPS infusion. Results showed that, in vivo, curcumin reduced the mortality rate of LPS-infused rats by decreasing the circulating TNF-alpha levels and the consumption of peripheral platelets and plasma fibrinogen. Furthermore, in vivo curcumin also has the effect of preventing the formation of fibrin deposition in the glomeruli of kidney. These results reveal the therapeutic potential of curcumin in infection-related coagulopathy of DIC.

TNF-α Associated Death Receptor Signaling in Aged Skeletal Muscle

Tumor necrosis factor-alpha (TNF-α) is a pro-apoptotic cytokine that is elevated in the serum of aged humans and animals. The TNF-α associated apoptotic pathway is initiated upon its binding to the type I TNF receptor with subsequent activation of a caspase cascade. Previous research has also demonstrated that changes in pro-apoptotic pathways are distinct within aged skeletal muscle. PURPOSE: To determine if the pro-apoptotic signaling pathway initiated by TNF-α is active within aged skeletal muscle, compared to young adult skeletal muscle. METHODS: Young adult (5–7 mo, n = 8) and aged (33 mo, n = 8) Fisher Brown Norway (FBN) rats were utilized in this study. The soleus muscles were excised and flash frozen in liquid nitrogen cooled in isopentane. Seventy-five milligram muscle samples were homogenized and prepared for RT-PCR as well as western-blot analyses for the following markers: the type I TNF receptor, FADD, TRADD, caspase-8 and caspase-3. The enzymatic activity for caspase-8 and caspase-3 were examined using specific fiuorometric substrates. The incidence of apoptosis was examined using a cell-death ELISA kit. Groups were analyzed using independent samples t-test with significance setap<0.05. RESULTS: The bodyweight of aged rats was 47% greater than young adult rats, while the absolute and normalized soleus weight was 15% less and 42% less, respectively. The apoptotic index was 3-fold greater in aged soleus muscles. The mRNA expression of the type I TNFR was 62% greater in aged muscle, while no changes in the protein content were observed. The mRNA and protein content of FADD were both 1 -fold greater in aged soleus muscles. No changes were noted in the mRNA expression for TRADD or caspase-3. The protein content of procaspase-8 was 70% less in aged skeletal muscle. The enzymatic activities of caspase-8 and caspase-3 were 33% and 20% greater in aged soleus muscles. CONCLUSIONS: The TNF-α apoptotic pathway is an active process within aged soleus muscle, as evidenced by the greater mRNA expression, protein content, and enzymatic activities of the components in this pathway. This pro-apoptotic pathway may contribute to muscle mass reductions typically observed as a result of aging, when circulating TNF-α levels are elevated. Funded by the ACSM Doctoral Student Research Grant (FRG-14) and NIH: NIA R01AG021530.

Tumour necrosis factor (TNF)α −308 G/G promoter polymorphism and TNFα levels correlate with a better response to adalimumab in patients with rheumatoid arthritis

Objective: To investigate the influence of −308 tumour necrosis factor‐α (TNFα) promoter polymorphism and circulating TNFα levels in the clinical response to adalimumab treatment in patients with rheumatoid arthritis (RA).Methods: Eighty‐one patients with active RA were genotyped for the −308 TNFα polymorphism by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) analysis and subdivided into two groups for each polymorphism (G/A and G/G genotype). All received 40 mg of adalimumab subcutaneously every other week. We compared the groups' clinical responses to adalimumab at 8, 16, and 24 weeks using the Disease Activity Score in 28 joints (DAS28).Results: Both groups showed a significant improvement from baseline. A significant difference between groups was found at week 24. We found that 88.2% of G/G versus 68.4% of G/A for the −308 polymorphism were DAS28 responders (p = 0.05). The score improvement at week 24 was 2.5±1.3 in the G/G group and 1.8±1.3 in the G/A group for the −308 polymorphism (p = 0.04). The median of serum TNFα levels of the G/A group were lower than those of the G/G group, and statistically different at weeks 8 and 24 (p<0.039 and p<0.043). When comparing baseline levels to those achieved at 8, 16, and 24 weeks for the whole group, only responder patients showed a statistically significant overall increase in TNFα over time (p<0.000001).Conclusion: A relationship between DAS28 improvement, the −308 G/G polymorphism, and increased circulating TNFα levels was found in Chilean RA patients treated with adalimumab.

Type D personality is associated with increased levels of tumour necrosis factor (TNF)-α and TNF-α receptors in chronic heart failure

Background Pro-inflammatory cytokines and their circulating receptors are powerful predictors of poor outcome in patients with chronic heart failure (CHF). We hypothesized that Type D personality, known to independently predict long-term mortality in patients with coronary heart disease, would relate to immune activation in CHF. Methods 91 stable CHF patients (79% males, mean age 57 ± 13 yrs, 58% ischemic heart disease) with left ventricular ejection fraction ≤ 35% completed a psychological questionnaire to assess Type D personality (i.e., the tendency to experience negative emotions and to inhibit their expression). Plasma levels of tumour necrosis factor (TNF)-α, soluble TNF-α receptor 1 and 2 (sTNFR1 and sTNFR2) and interleukin-6 (IL-6) were measured by ELISA. Results Type D patients ( n = 30) had higher levels of TNF-α (5.1 ± 2.9 versus 3.9 ± 2.6 pg/ml, p = 0.066), sTNFR1 (1656 ± 1057 versus 1098 ± 424 pg/ml, p = 0.009) and sTNFR2 (2869 ± 1510 versus 2011 ± 794 pg/ml, p = 0.006) as compared to non-Type D patients ( n = 61), whereas IL-6 was not different. After controlling for sex, age, ischemic etiology and disease severity, multivariate analysis yielded Type D as the strongest predictor of increased TNF-α (OR = 2.9, p = 0.048) and sTNFR2 levels (OR = 3.9, p = 0.018). For sTNFR1, the effect of Type D was no longer significant in this analysis (OR = 2.7, p = 0.112). Conclusions Type D personality was independently associated with increased circulating levels of TNF-α and sTNFR2 in patients with CHF. This study provides the strongest evidence to date that chronic emotional distress may be associated with immune activation in heart failure.

Increased productivity of tumor necrosis factor-alpha in helper T cells in patients with systolic heart failure

Background and aims Whereas increased circulating proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), play an important role in heart failure, where and how TNF-α production is upregulated remains largely unknown. We studied the productivity of TNF-α in peripheral lymphocytes and underlying mechanisms in patients with heart failure. Methods Symptomatic NYHA II–IV patients with chronic heart failure with systolic dysfunction ( n = 39, aged 74 ± 11, ejection fraction [EF] ≦ 50%) were compared with asymptomatic NYHA I patients ( n = 18, aged 72 ± 10, EF > 50%) and normal subjects ( n = 15, aged 67 ± 11). Lymphocyte subsets (CD3, CD4, and CD8) and intracellular production of TNF-α in peripheral leukocytes were quantified by immunofluorescent flow cytometry, and relationships between these parameters and circulating proinflammatory cytokines were analyzed. Results Subpopulation of TNF-α-producing CD4 was larger in NYHA II–IV patients (23.7% [18.0–28.6]) than in normal subjects (17.1% [6.5–19.5], p < 0.05) and was correlated with plasma TNF-α levels ( r = 0.26, p < 0.05), EF ( r = − 0.26, p < 0.05), CD4/CD8 ratios ( r = 0.42, p < 0.001), and subpopulation of TNF-α-producing monocytes ( r = 0.47, p < 0.0001). Plasma levels of soluble CD14 and interleukin-12 (IL-12) were significantly higher in NYHA II–IV patients than in normal subjects (1971 ng/mL [1740–2375] vs. 1607 ng/mL [1530–1930], p < 0.01; and 121 pg/mL [62–230] vs. 62 pg/mL [54–99], p < 0.05, respectively), and plasma IL-12 levels were correlated with plasma TNF-α levels ( r = 0.41, p < 0.001). Conclusions Increased productivity of TNF-α in helper T cells, associated with their dominance over cytotoxic T cells, may partially contribute to an increase in circulating TNF-α levels in heart failure.

Role of Lipopolysaccharide and Cecal Ligation and Puncture on Blood Coagulation and Inflammation in Sensitive and Resistant Mice Models

The hemostatic system is severely disturbed during endotoxemia, leading to a hypercoagulable state. However, it remains uncertain to what extent hypercoagulability is the critical factor in determining the clinical course rather than just the consequence of a severe systemic inflammatory response. To answer this question, we evaluated the evolution of hemostatic and inflammatory markers, as well as histological features, in mice sensitive and resistant to two models of endotoxemia: lipopolysaccharide-injection and cecal ligation puncture. Genetic (knockout mice) and pharmacological (PJ34) blockade of the nuclear enzyme PARP-1 was used to achieve resistance to the endotoxemia. In both models, endotoxemia resulted in antithrombin deficiency, decreased platelets, and fibrin deposition in organs, which were similar in all groups of mice. By contrast, proinflammatory mediators, inflammatory cell infiltration (especially that mediated by mononuclear cells), and organ degeneration were more intense in sensitive animals. Further studies supported a negative role for the triggering of the coagulation cascade in the mortality associated with the endotoxic shock. Hirudin had a minor effect on cell infiltration and organ damage, despite causing a potent inhibition of fibrin deposition. On the other hand, a sublethal dose of lipopolysaccharide yielded significant fibrin deposition but weak activation of the inflammatory response. Our results suggest that activation of coagulation by endotoxemia is severe and independent of the inflammatory response. However, such activation may act with fibrin deposition to have a minor influence on survival in sepsis.

Effect of AT1 receptor antagonism on vascular and circulating inflammatory mediators in SHR: role of NF-kappaB/IkappaB system.

We investigated the role of angiotensin II in vascular and circulating inflammatory markers in spontaneously hypertensive rats (SHR). IL-1beta, IL-6, and TNF-alpha aortic mRNA expression and plasma levels were measured in adult SHR untreated or treated with the angiotensin II receptor antagonist candesartan (2 mg.kg(-1).day(-1)) or antihypertensive triple therapy (TT; in mg.kg(-1).day(-1): 20 hydralazine + 7 type 1 hydrochlorothiazide + 0.15 reserpine) for 10 wk. Likewise, aortic expression of NF-kappaB p50 subunit precursor p105 and its inhibitor (IkappaB) were measured. Age-matched Wistar-Kyoto rats (WKY) served as normotensive reference. High blood pressure levels were associated with increased (P < 0.05) aortic mRNA expression of IL-1beta, IL-6, and TNF-alpha. Hypertension was also accompanied by increased IL-1beta and IL-6 plasma levels. No differences were observed in circulating TNF-alpha levels between SHR and WKY. SHR presented elevated aortic mRNA expression of the transcription factor NF-kappaB and reduction in its inhibitor, IkappaB. Candesartan decreased (P < 0.05) blood pressure levels, aortic mRNA expression of IL-1beta, IL-6, and TNF-alpha, and (P < 0.05) IL-1beta and IL-6 plasma concentration. However, although arterial pressure decrease was comparable for the treatments, TT only partially reduced the increments in inflammatory markers. In fact, candesartan-treated rats showed significantly lower levels of circulating and vascular inflammatory markers than TT-treated animals. The treatments increased IkappaB mRNA expression similarly. However, only candesartan reduced NF-kappaB mRNA expression. In summary, 1) SHR presented a vascular inflammatory process; 2) angiotensin II, and increased hemodynamic forces associated with hypertension, seems to be involved in stimulation of inflammatory mediators through NF-kappaB system activation; and 3) reduction of inflammatory mediators produced by candesartan in SHR could be partially due to both downregulation of NF-kappaB and upregulation of IkappaB.

Leptin and TNF-Alpha Levels in Patients with Chronic Obstructive Pulmonary Disease and Their Relationship to Nutritional Parameters

Background: Leptin is a protein mainly secreted by adipocytes, and the major function of leptin was its role in body weight regulation. In humans, there was a strong correlation between leptin and nutritional parameters, such as body mass index (BMI) and fat mass (FM). Administration of recombinant leptin to ob/ob mice, which have a genetic defect in leptin production, reduces food intake, increases energy expenditure, and decreases body weight. It is suggested that increased levels of circulating leptin levels may contribute to anorexia and weight loss in pathologic conditions including chronic obstructive pulmonary disease (COPD). Recent studies have provided evidence for a link between leptin and proinflammatory cytokines such as TNF-α. Objective: This study aimed to detect serum leptin and TNF-α levels in COPD patients without weight loss during stable disease and acute exacerbation, and to investigate relationships between leptin, TNF-α and nutritional parameters at different stages of the disease. Material and Methods: 26 stable COPD patients, 16 COPD patients with acute exacerbation and 15 control subjects participated in this study. To eliminate the effects of sex differences, all patients and controls were male. BMI, percent ideal body weight, percent FM, sum of skinfold tickness and serum leptin and TNF-α levels were measured in all participants. Leptin and TNF-α levels were measured by ELISA. Results: Serum leptin and TNF-α levels were significantly higher in the patients experiencing exacerbation than in the stable patients and controls. Although leptin levels were lower and TNF-α levels were higher in the stable patient group than in the controls, these differences were not statistically different. Leptin levels were significantly correlated with the nutritional parameters in both control and stable groups. However, in patients with acute exacerbation, a correlation between leptin and nutritional parameters was not found. There was no significant relationship between TNF-α and nutritional parameters in the three groups. In addition, while there was no correlation between leptin and TNF-α levels in the stable and control groups, a significant positive correlation was observed in patients with exacerbation. Conclusion: In conclusion (1) elevated TNF-α levels may be related to increased inflammation in patients, (2) circulating TNF-α levels were associated with increased leptin levels and (3) although leptin and nutritional parameters were correlated in the stable COPD patients, the correlation was weaker compared to controls, and during an exacerbation it disappeared completely. Therefore, inappropriately increased levels of leptin and TNF-α noted during recurrent acute exacerbations in patients with COPD may lead to changes in nutritional parameters and body weight in the course of the disease.

Cytokines and immune activation in systolic heart failure: the role of Type D personality

The proinflammatory cytokine tumor necrosis factor-α (TNF-α) and its soluble receptors 1 (sTNFR1) and 2 (sTNFR2) are predictors of mortality in chronic heart failure (CHF) but the determinants of these increased levels of disease-promoting cytokines are largely unknown. Type D personality refers to the combination of the tendency to experience negative emotions (negative affectivity) and the tendency to inhibit the expression of emotions in social interaction (social inhibition). Type D is an independent predictor of cardiac events in coronary patients who are at risk for CHF. The present study examined the effect of Type D personality on TNF-α, sTNFR1, and sTNFR2 in 42 men with CHF ( mean age =57.9±10.5 years). There was a significant multivariate effect of Type D on TNF-α measures ( p=.006); i.e., circulating levels of TNF-α (4.8±0.9 versus 2.5±0.2 pg/ml , p=.003), sTNFR1 (1814±314 versus 1134±78 pg/ml , p=.014), and sTNFR2 (2465±243 versus 1874±118 pg/ml , p=.019) were significantly higher in Type D patients as compared to non-Type D patients. The effect size (ES) of Type D personality ranged from rather large (sTNFR1, ES=0.77; sTNFR2, ES= 0.73) to large (TNF-α, ES=0.90). After controlling for ischemic etiology and severity of heart failure, Type D personality emerged as an independent predictor of increased circulating levels of both TNF-α (OR=9.5, 95% CI 2.1–43.8, p=.004) and TNF-α receptors (OR= 6.1, 95% CI 1.4–25.8, p=.014). These findings are consistent with the prognostic power of Type D personality regarding long-term morbidity and mortality in patients with established coronary heart disease. This study suggests that individual differences in personality contribute to the psychoneuroimmunological aspects of heart failure.

Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis

Activation of macrophages by endotoxin is assumed responsible for increased circulating tumor necrosis factor α (TNF-α) and soluble TNF receptor (sTNFR) levels in cirrhosis. Relevant to this is expression of Toll-like receptor (TLR) 4 and TLR2, which is critically involved in production of TNF-α in response to endotoxin and Gram-positive microbial stimuli, respectively. The first studies on this in cirrhosis are reported here. In 36 cirrhotic patients and 32 controls, we measured (1) circulating endotoxin, TNF-α, and sTNFR levels; (2) peripheral blood mononuclear cell (PBMC) expression of TLR4 and TLR2, and (3) in vitro TNF-α production by PBMCs stimulated with endotoxin or Staphylococcus aureus enterotoxin B (SEB). PBMC expression of TLR2, circulating TNF-α levels, and in vitro TNF-α production were reassessed after supplementation with a synbiotic regimen known to increase intestinal levels of Gram-positive bacteria. Endotoxin, TNF-α, and sTNFR levels were significantly increased in cirrhosis. Endotoxin levels did not correlate significantly with other parameters. PBMC expression of TLR2 but not TLR4 was significantly up-regulated in cirrhosis and correlated significantly with serum TNF-α and sTNFR levels. In vitro TNF-α production by PBMCs stimulated by SEB was significantly blunted. Supplementation with the synbiotic regimen resulted in significant up-regulation of PBMC expression of TLR2. Serum TNF-α levels were further increased and in vitro TNF-α production further reduced in most patients. In conclusion, up-regulation of PBMC expression of TLR2 but not TLR4 occurs in cirrhosis, which implies, contrary to previous assumptions, an important stimulatory role for Gram-positive microbial components but not endotoxin. TLR2 likely contributes to increased circulating TNF-α and sTNFR levels in cirrhosis. H epatology 2003;37:1154-1164.)

High Circulating Levels of Tumor Necrosis Factor-α in Centenarians Are Not Associated with Increased Production in T Lymphocytes

Background: Aging is characterized by increased inflammatory activity reflected by increased plasma levels of proinflammatory cytokines, concomitant with an altered cytokine profile of T lymphocytes. High plasma levels of tumor necrosis factor (TNF)-α are strongly associated with morbidity and mortality in elderly humans. However, the cellular source and mechanisms for the increased circulating TNF-α levels are unknown. Objective: The aim of the present study was to investigate if high plasma levels of TNF-α are associated with increased production of TNF-α by T lymphocytes in elderly humans. Methods: TNF-α production by CD4+ and CD8+ T lymphocytes was measured by flow cytometry following stimulation with phorbol 12-myristate 13-acetate and ionomycin in 28 young controls, 14 81-year-olds and 25 centenarians. Results: Plasma levels of TNF-α increased with increasing age. An increased percentage and number of T lymphocytes from the 81 year olds expressed TNF-α, whereas centenarians did not show this altered TNF-α secretion profile. Conclusion: T cells may contribute to the elevated levels of plasma TNF-α in healthy elderly subjects, whereas other mechanisms are responsible in very old individuals.

Cellular remodeling in heart failure disrupts K(ATP) channel-dependent stress tolerance.

ATP-sensitive potassium (K(ATP)) channels are required for maintenance of homeostasis during the metabolically demanding adaptive response to stress. However, in disease, the effect of cellular remodeling on K(ATP) channel behavior and associated tolerance to metabolic insult is unknown. Here, transgenic expression of tumor necrosis factor alpha induced heart failure with typical cardiac structural and energetic alterations. In this paradigm of disease remodeling, K(ATP) channels responded aberrantly to metabolic signals despite intact intrinsic channel properties, implicating defects proximal to the channel. Indeed, cardiomyocytes from failing hearts exhibited mitochondrial and creatine kinase deficits, and thus a reduced potential for metabolic signal generation and transmission. Consequently, K(ATP) channels failed to properly translate cellular distress under metabolic challenge into a protective membrane response. Failing hearts were excessively vulnerable to metabolic insult, demonstrating cardiomyocyte calcium loading and myofibrillar contraction banding, with tolerance improved by K(ATP) channel openers. Thus, disease-induced K(ATP) channel metabolic dysregulation is a contributor to the pathobiology of heart failure, illustrating a mechanism for acquired channelopathy.

High tumor necrosis factor-α levels in the patients with Epstein–Barr virus-associated peripheral T-cell proliferative disease/lymphoma

We have attempted to find out any relationships between circulating tumor necrosis factor (TNF)-α levels and Epstein–Barr virus (EBV) associated peripheral T-cell and NK-cell proliferative disease/lymphoma (PTPD/L) status. The distribution of TNF-α level was significantly higher ( P<0.05) in patients than in controls. Patients carrying EBV genome in their peripheral T-cells showed higher TNF-α levels than the patients with EBV negative peripheral T-cells ( P<0.001). Among patients whose peripheral T-cells were positive for EBV genome, TNF-α levels between the wild type LMP-1 gene carriers and the 30-bp deletion type LMP-1 gene carriers were compared and the wild type LMP-1 gene carrier group showed significantly higher TNF-α levels ( P<0.01). As for the outcome of the patients and TNF-α levels, significant differences were observed between dead and alive with disease group ( P<0.001), and dead and alive with complete remission group ( P<0.01). Since circulating TNF-α levels in PTPD/L patients correlate with the disease and EBV infection status, it may be possible that monitoring of the TNF-α levels will be a useful prognostic marker.

Anti-inflammatory properties of molecular hydrogen: investigation on parasite-induced liver inflammation

Molecular hydrogen reacts with the hydroxyl radical, a highly cytotoxic species produced in inflamed tissues. It has been suggested therefore to use gaseous hydrogen in a new anti-inflammatory strategy. We tested this idea, with the aid of the equipment and skills of COMEX SA in Marseille, a group who experiments with oxygen–hydrogen breathing mixtures for professional deep-sea diving. The model used was schistosomiasis-associated chronic liver inflammation. Infected animals stayed 2 weeks in an hyperbaric chamber in a normal atmosphere supplemented with 0.7 MPa hydrogen. The treatment had significant protective effects towards liver injury, namely decreased fibrosis, improvement of hemodynamics, increased NOSII activity, increased antioxidant enzyme activity, decreased lipid peroxide levels and decreased circulating TNF-α levels. Under the same conditions, helium exerted also some protective effects, indicating that hydroxyl radical scavenging is not the only protective mechanism. These findings indicate that the proposed anti-inflammatory strategy deserves further attention.

Clinical implications of tumour necrosis factor α antagonism in patients with congestive heart failure

Tumour necrosis factor (TNF) α is a pro-inflammatory cytokine that is produced by the heart under certain forms of stress. Patients with advanced heart failure have increased levels of circulating...

Aspiration Pneumonia-Induced Sepsis Increases Cardiac Dysfunction after Burn Trauma

Pneumonia occurs in approximately 50% of intubated patients in burn intensive care units and carries a mortality as high as 40%. A model was developed to study altered cardiopulmonary function in burn complicated by pneumococcal pneumonia. Sprague–Dawley rats were given a 43% total body surface area scald burn or sham burn; 24 h later they were transtracheally inoculated with either 107Streptococcus pneumoniaein 0.5 ml phosphate buffer solution (PBS) or 0.5 ml PBS alone. The four groups were: Sham (N= 7), Burn alone (N= 10), Pneumonia alone (N= 11), and Burn and Pneumonia (N= 12). A fifth group of burned rats (N= 10), given an identical fluid resuscitation regimen, was sacrificed 24 h postburn to examine the early cardiac responses to burn injury alone. Shams and burned animals had normal lung histology, negative bronchoalveolar lavage (BAL) cultures, and negative blood cultures. Pneumonia and burn plus pneumonia animals had abnormal lung histology, positive BAL cultures, and positive blood cultures. Cardiac function was assessed 24 h afterS. pneumoniaechallenge (48 h after burn) (Langendorff preparation). Compared to the Sham group, Pneumonia group, and Burn group, the Burn plus Pneumonia group had the lowest left ventricular pressure (LVP: 94 ± 4, 71 ± 3, and 87 ± 3 mm Hg vs 63 ± 4 mm Hg,P< 0.05), the lowest maximal rate of LVP rise (+dP/dtmax: 1932 ± 115, 1419 ± 71, and 1772 ± 96 mm Hg vs 1309 ± 59 mm Hg/s,P< 0.05), and the lowest maximal rate of LVP fall (−dP/dtmax: 1704 ± 120, 1263 ± 73, and 1591 ± 83 mm Hg vs 1025 ± 98 mm Hg/s,P< 0.05). Cardiac contraction and relaxation deficits were confirmed in animals 24 h postburn (group 5), as indicated by a significantly lower LVP and ±dP/dtmax(62 ± 3 mm Hg, 1210 ± 60, and 909 ± 50 mm Hg/s, respectively,P< 0.05 compared to Sham group). Tumor necrosis factor-alpha (TNF-α) concentrations in serum, but not bronchoalveolar lavage, were greater in burned animals with aspiration pneumonia-induced sepsis than in animals with either burn alone or aspiration pneumonia-induced sepsis alone. While our data suggest that elevated circulating TNF-α levels may contribute, in part, to depressed cardiac function, further studies are needed to fully define the mechanisms underlying cardiac contractile deficits in this model. We speculate that depressed cardiopulmonary function due to burn complicated by pneumonia and sepsis contributes to the high mortality of this patient population.

METFORMIN INCREASES CIRCULATING TUMOUR NECROSIS FACTOR α LEVELS IN NON-OBESE NON-DIABETIC PATIENTS WITH CORONARY HEART DISEASE

Metformin reduces insulin resistance and hyperinsulinaemia, as well as lipid levels and body weight. The mechanisms behind these effects are likely to involve intracellular insulin signalling. Recent evidence implicates tumour necrosis factor α (TNF-α) as a modulatory factor on insulin resistance. The present investigation was undertaken to clarify whether metformin affects TNF-α and soluble TNF receptor levels. Sixty non-diabetic men with coronary heart disease were treated with diet and lifestyle advice and lovastatin 40 mg/day during a 4-week run-in period. During this period TNF-α and soluble TNF receptor p75 remained unchanged, whereas soluble TNF receptor p55 increased by 8% (P<0.05). Twelve weeks of metformin treatment increased TNF-α by 33% (P<0.05). This effect was restricted to non-obese patients in whom TNF-α increased by 68% (P<0.01). Soluble TNF receptors p55 and p75 remained unchanged in the whole group, whereas soluble TNF receptor p55 increased by 11% (P<0.05) in non-obese patients. Since metformin reduces insulin resistance both in obese and non-obese subjects but increases TNF-α levels only in the latter, it is concluded that the drug does not exert its effect on insulin resistance through regulation of circulating TNF-α levels.