Early Neonatal C-Reactive Protein Levels and Periventricular Leukomalacia.

BACKGROUND: Cystic periventricular leukomalacia (cPVL) is a strong indicator of subsequent motor and developmental impairments in premature infants. There is a paucity of publications on biomarkers of cPVL. OBJECTIVES: To determine C-reactive protein (CRP) levels during the first week of life of preterm infants who later developed cPVL and to identify the association between CRP levels with perinatal factors. METHODS: We retrospectively included infants ≤ 32 weeks gestation and/or birth weights ≤ 1500 grams; 17 with a cranial ultrasound diagnosis of cPVL and 54 with normal ultrasounds. Serum CRP levels were measured during days 1-7 (CRP1-7d) of life and subdivided into two timing groups: days 1-3 (CRP1-3d) and days 4-7 (CRP4-7d). RESULTS: The cPVL group had significantly higher mean CRP4-7d levels compared to controls (12.75 ± 21.2 vs. 2.23 ± 3.1, respectively, P = 0.03), while CRP1-3d levels were similar. CRP1-7d levels were significantly correlated with maximal fraction of inspired oxygen during the first 12 hours of life (FiO2-12h, r = 0.51, P < 0.001]. Additional risk factors were not associated with CRP levels. CONCLUSIONS: Our finding of elevated CRP4-7d levels and later development of cPVL supports earlier studies on the involvement of inflammation in the pathogenesis of cPVL. Whether CRP could serve as a biomarker of cPVL and its correlation with outcomes, awaits further trials. Furthermore, the correlation between FiO2-12h and CRP1-7d levels suggest that hypoxia and/or hyperoxia may serve as a trigger in the activation of inflammation during the first days of life of preterm infants.

The Role of the Pathogen Dose and PI3Kγ in Immunometabolic Reprogramming of Microglia for Innate Immune Memory.

Microglia, the innate immune cells of the CNS, exhibit long-term response changes indicative of innate immune memory (IIM). Our previous studies revealed IIM patterns of microglia with opposing immune phenotypes: trained immunity after a low dose and immune tolerance after a high dose challenge with pathogen-associated molecular patterns (PAMP). Compelling evidence shows that innate immune cells adopt features of IIM via immunometabolic control. However, immunometabolic reprogramming involved in the regulation of IIM in microglia has not been fully addressed. Here, we evaluated the impact of dose-dependent microglial priming with ultra-low (ULP, 1 fg/mL) and high (HP, 100 ng/mL) lipopolysaccharide (LPS) doses on immunometabolic rewiring. Furthermore, we addressed the role of PI3Kγ on immunometabolic control using naïve primary microglia derived from newborn wild-type mice, PI3Kγ-deficient mice and mice carrying a targeted mutation causing loss of lipid kinase activity. We found that ULP-induced IIM triggered an enhancement of oxygen consumption and ATP production. In contrast, HP was followed by suppressed oxygen consumption and glycolytic activity indicative of immune tolerance. PI3Kγ inhibited glycolysis due to modulation of cAMP-dependent pathways. However, no impact of specific PI3Kγ signaling on immunometabolic rewiring due to dose-dependent LPS priming was detected. In conclusion, immunometabolic reprogramming of microglia is involved in IIM in a dose-dependent manner via the glycolytic pathway, oxygen consumption and ATP production: ULP (ultra-low-dose priming) increases it, while HP reduces it.

Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and postexertional malaise. There is little known about the metabolism of specific immune cells in patients with ME/CFS. To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 patients with ME/CFS and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism and plasma cytokines. We found that ME/CFS CD8+ T cells had reduced mitochondrial membrane potential compared with those from healthy controls. Both CD4+ and CD8+ T cells from patients with ME/CFS had reduced glycolysis at rest, whereas CD8+ T cells also had reduced glycolysis following activation. Patients with ME/CFS had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from correlations seen in healthy control subjects. Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.

Tumor-derived TGF-ß inhibits mitochondrial respiration to suppress IFN-γ production by human CD4+ T cells.

Transforming growth factor-ß (TGF-ß) is produced by tumors, and increased amounts of this cytokine in the tumor microenvironment and serum are associated with poor patient survival. TGF-ß-mediated suppression of antitumor T cell responses contributes to tumor growth and survival. However, TGF-ß also has tumor-suppressive activity; thus, dissecting cell type-specific molecular effects may inform therapeutic strategies targeting this cytokine. Here, using human peripheral and tumor-associated lymphocytes, we investigated how tumor-derived TGF-ß suppresses a key antitumor function of CD4+ T cells, interferon-γ (IFN-γ) production. Suppression required the expression and phosphorylation of Smad proteins in the TGF-ß signaling pathway, but not their nuclear translocation, and depended on oxygen availability, suggesting a metabolic basis for these effects. Smad proteins were detected in the mitochondria of CD4+ T cells, where they were phosphorylated upon treatment with TGF-ß. Phosphorylated Smad proteins were also detected in the mitochondria of isolated tumor-associated lymphocytes. TGF-ß substantially impaired the ATP-coupled respiration of CD4+ T cells and specifically inhibited mitochondrial complex V (ATP synthase) activity. Last, inhibition of ATP synthase alone was sufficient to impair IFN-γ production by CD4+ T cells. These results, which have implications for human antitumor immunity, suggest that TGF-ß targets T cell metabolism directly, thus diminishing T cell function through metabolic paralysis.

Effect of moderate exercise under hypoxia on Th1/Th2 cytokine balance.

INTRODUCTION AND OBJECTIVE: Moderate exercise performed in normoxia can be immunostimulatory, while strenuous exercise can be immunosuppressive. However, less is known about the effects of exercise under hypoxia on cytokines. The aim of this study was to evaluate the effects of an acute exercise session performed under hypoxia similar to an altitude of 4200 m on cytokine balance. Our hypothesis was that exercise, even of moderate intensity, associated with hypoxia may induce different changes in relation to the normoxic condition. METHODS: Eight healthy male volunteers were exercised on a treadmill for 1 hour at an intensity of 50% VO2peak under normoxic or hypoxic condition (4200 m). Blood samples were collected at rest and immediately 1 hour after the exercise, respectively to determine cytokines, hormones and metabolites. The two-way ANOVA and the Bonferroni post hoc test were used and the significance adopted was P < .05. RESULTS: While IL-2, the IL-2/IL-4 ratio and glutamine decreased under hypoxia, IL-6 and IL-1ra increased. There were increases in the IL-2/IL-4 ratio, IL-6, IL-1ra and IL-10/TNF-α in normoxia. There were no differences in cortisol or glucose. CONCLUSION: Moderate exercise under hypoxia condition changes the Th1/Th2 balance including IL-2, IL-4 and TNF-α cytokines, suggesting a Th2 response after 1 hour rest.

Determining Macrophage Polarization upon Metabolic Perturbation.

Metabolic reprograming controlling macrophage activation and function is emerging as new regulatory circuit on shaping immune responses. Generally, lipopolysaccharides (LPS)-induced pro-inflammatory activated macrophages, known as M1 macrophages, display higher glycolysis. In contrast, interleukin-4 (IL-4)-skewed anti-inflammatory activated macrophages, known as M2 macrophages, mainly rely on oxidative phosphorylation for their bioenergetic demands. Emerging evidence reveals that these metabolic preferences further fine-tune macrophage polarization process, including signaling cascades and epigenetic reprogramming. Thus, specific nutrient microenvironments may affect inflammatory responses of macrophages by intervening these metabolic machineries. How to measure the metabolic switch of macrophages both in vitro and in vivo is an important issue for understanding immunometabolic regulations in macrophages. Here, we describe a basic protocol for examining how glutamine metabolism affects macrophage polarization by using the Extracellular Flux (XF(e)96) Analyzer (Seahorse Bioscience), which takes real-time measurements of oxidative phosphorylation and glycolysis. We also present a detailed procedure for detecting the expression of inflammatory genes in polarized macrophages under glutamine-replete or -deprived conditions.

Better approach for autoimmune pulmonary alveolar proteinosis treatment: inhaled or subcutaneous granulocyte-macrophage colony-stimulating factor: a meta-analyses.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare pulmonary disease caused by functional deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF therapy in aPAP has been reported effective in some studies. This meta-analyses aimed to evaluate whether GM-CSF therapy, including inhaled and subcutaneous GM-CSF have therapeutic effect in aPAP patients. METHODS: We analyzed 10 studies searched from PubMed, EmBase, Web of Science, Wiley Online Library and Cochrane Collaboration databases to evaluate the pooled effects of GM-CSF treatment in aPAP patients. RESULTS: Ten observational studies involving 115 aPAP patients were included. The pooled analyses of response rate (81%, p < 0.001), relapse rate (22%, p = 0.009), PaO2 (13.76 mmHg, p < 0.001) and P(A-a)O2 (19.44 mmHg, p < 0.001) showed that GM-CSF treatment was effective on aPAP patients. Further analyses showed that inhaled GM-CSF treatment was more effective than subcutaneous GM-CSF therapy, including a higher response rate (89% vs. 71%, p = 0.023), more improvements in PaO2 (21.02 mmHg vs. 8.28 mmHg, p < 0.001) and P(A-a)O2 (19.63 mmHg vs. 9.15 mmHg, p < 0.001). CONCLUSIONS: As two routes of exogenous GM-CSF treatment, inhaled and subcutaneous were both proven to have effect on aPAP patients. Furthermore, inhaled GM-CSF therapy showed a higher response rate, more improvements on PaO2 and P(A-a)O2 than subcutaneous GM-CSF treatment in aPAP patients, suggesting inhaled GM-CSF therapy could have more benefits on aPAP patients. Therefore, GM-CSF therapy, especially inhaled GM-CSF, might be a promising therapeutic option in treating aPAP.

Nur77 serves as a molecular brake of the metabolic switch during T cell activation to restrict autoimmunity.

T cells critically depend on reprogramming of metabolic signatures to meet the bioenergetic demands during activation and clonal expansion. Here we identify the transcription factor Nur77 as a cell-intrinsic modulator of T cell activation. Nur77-deficient T cells are highly proliferative, and lack of Nur77 is associated with enhanced T cell activation and increased susceptibility for T cell-mediated inflammatory diseases, such as CNS autoimmunity, allergic contact dermatitis and collagen-induced arthritis. Importantly, Nur77 serves as key regulator of energy metabolism in T cells, restricting mitochondrial respiration and glycolysis and controlling switching between different energy pathways. Transcriptional network analysis revealed that Nur77 modulates the expression of metabolic genes, most likely in close interaction with other transcription factors, especially estrogen-related receptor α. In summary, we identify Nur77 as a transcriptional regulator of T cell metabolism, which elevates the threshold for T cell activation and confers protection in different T cell-mediated inflammatory diseases.

Metabolic regulation of macrophages in tissues.

Macrophages are innate immune cells that provide host defense and have tissue-specific roles in the maintenance of organ homeostasis and integrity. In most cases macrophages keep us healthy but when their balanced response to damage or homeostatic signals is perturbed, they can drive chronic inflammatory responses and pathology. To fulfil their broad range of functions, macrophages adopt a plethora of activation states. Understanding their regulation and phenotypic heterogeneity is crucial because macrophages are critical in many diseases. Consequently, macrophages have emerged as attractive targets for therapy of diseases in which they determine disease outcome, such as cardiovascular disease, cancer and other Western killer diseases. Recent advances in the flourishing field of immunometabolism highlight that the metabolic profile of macrophages directly regulates their activation status and associated functions. In this short review, we summarize how recent research on the metabolic regulation of macrophages has vividly improved our understanding of macrophage activation. Most of our existing knowledge results from in vitro studies with murine bone marrow-derived macrophages which can't fully grasp the complexity of (micro)environmental control of macrophages in tissues. We therefore highlight current weaknesses and missing links in macrophage immunometabolism research and provide future directions to make the step from the well-controlled plastic in vitro cell culture systems to the complex in vivo tissue environment.

Neutrophils and inflammatory resolution in the mucosa.

Inflammatory diseases in mucosal organs as diverse as the lung, liver and intestine inevitably require the intimate interactions between neutrophils and epithelia. The physiologic consequences of such interactions often determine endpoint organ function, and for this reason, much recent interest has developed in identifying mechanisms and novel targets to promote the resolution of mucosal inflammation. Physiologically-relevant in vitro and in vivo model systems have aided in discovery of novel pathways to define basic inflammatory mechanisms and approaches to defining the concepts of inflammatory resolution. Here, we will review the recent literature regarding the contribution of neutrophils to inflammatory resolution, with an emphasis on the role of the tissue microenvironment, endogenous pathways for promoting resolution and the molecular determinants of neutrophil-epithelial cell interactions during ongoing inflammation. These recent studies highlight the dynamic nature of pro-resolving pathways and lend insight into the complexity of treating mucosal inflammation.

Impact of brief exercise on peripheral blood NK cell gene and microRNA expression in young adults.

Natural killers (NK) cells are unique innate immune cells that increase up to fivefold in the circulating blood with brief exercise and are known to play a key role in first-response defense against pathogens and cancer immunosurveillance. Whether exercise alters NK cell gene and microRNA (miRNA) expression is not known. Thirteen healthy men (20-29 yr old) performed ten 2-min bouts of cycle ergometer exercise at a constant work equivalent to an average of 77% of maximum O2 consumption interspersed with 1-min rest. Blood was drawn before and immediately after the exercise challenge. NK cells were isolated from peripheral blood mononuclear cells using a negative magnetic cell separation method. We used Affymetrix U133+2.0 arrays for gene expression and Agilent Human miRNA V2 Microarray for miRNAs. A stringent statistical approach (false discovery rate < 0.05) was used to determine that exercise significantly altered the expression of 986 genes and 23 miRNAs. Using in silico analysis, we found exercise-related gene pathways where there was a high likelihood of gene-miRNA interactions. These pathways were predominantly associated with cancer and cell communication, including p53 signaling pathway, melanoma, glioma, prostate cancer, adherens junction, and focal adhesion. These data support the hypothesis that exercise affects the gene and miRNA expression pattern in the population of NK cells in the circulation and suggest mechanisms through which physical activity could alter health through the innate immune system.

Hypoxia-inducible factor-2α regulates GM-CSF-derived soluble vascular endothelial growth factor receptor 1 production from macrophages and inhibits tumor growth and angiogenesis.

Macrophage secretion of vascular endothelial growth factor (VEGF) in response to the hypoxic tumor microenvironment contributes to tumor growth, angiogenesis, and metastasis. We have recently demonstrated that macrophages stimulated with GM-CSF at low O(2) secrete high levels of a soluble form of the VEGF receptor 1 (sVEGFR-1), which neutralizes VEGF and inhibits its biological activity. Using small interfering RNA targeting to deplete hypoxia-inducible factor (HIF)-1α or HIF-2α in murine macrophages, we found that macrophage production of sVEGFR-1 in response to low O(2) was dependent on HIF-2α, whereas HIF-1α specifically regulated VEGF production. In our current report, we evaluated the growth of B16F10 malignant melanoma in mice with a monocyte/macrophage-selective deletion of HIF-1α or HIF-2α (HIF-1α(flox/flox)- or HIF-2α(flox/+)/LysMcre mice). GM-CSF treatment increased intratumoral VEGF and sVEGFR-1 in control mice, an effect that was associated with a decrease in microvessel density. GM-CSF treatment of HIF-1α(flox/flox)/LysMcre mice induced sVEGFR-1 but not VEGF, resulting in an overall greater reduction in tumor growth and angiogenesis compared with control mice. In addition, real-time PCR for melanoma-specific genes revealed a significantly reduced presence of lung micrometastases in HIF-1α(flox/flox)/LysMcre mice treated with GM-CSF. Conversely, GM-CSF treatment induced VEGF but not sVEGFR-1 in HIF-2α(flox/+)/LysMcre mice, and, correspondingly, GM-CSF did not decrease tumor growth, angiogenesis, or lung metastasis in these mice. This study reveals opposing roles for the HIFs in the regulation of angiogenesis by tumor-associated macrophages and suggests that administration of GM-CSF might be an effective means of inducing sVEGFR-1 and inhibiting tumor growth and angiogenesis in patients with melanoma.

Induction of HIF-1alpha and the glycolytic pathway alters apoptotic and differentiation profiles of activated human T cells.

The majority of in vitro studies involving lymphocytes is performed in AtmO(2), and the PhysO(2) that T cells encounter are variable but commonly much lower. Previous studies showed changed kinetics and delayed proliferation of human T cells at PhysO(2). Here, we show that CD3/CD28-dependent T cell activation induces faster cell cycling at AtmO(2) than at PhysO(2) (here taken to be 2%). Concomitantly with HIF-1alpha expression, we observed a switch in the T cell respiratory pathway toward glycolysis at PhysO(2). Thus, modulating available glucose levels showed that at PhysO(2), T cells rely more on glycolysis, associated with a higher phosphorylation of Akt(ser473). Although no difference in spontaneous apoptosis of resting cells was detected, it was increased significantly at PhysO(2) after T cell activation and was different within the different T cell subsets. This may explain at least partly the differently altered proliferation and subset distribution observed in CD4+ and CD8+ T cells as a result of differences in naïve and memory subset distribution. Together, these findings suggest that T cell activation thresholds, subsequent proliferative capacity, and susceptibility to apoptosis, hitherto studied in air and thought to be crucial for monitoring immune responsiveness, may require re-assessment.

The association between metabolic rate, immune parameters, and growth performance of rainbow trout, Oncorhynchus mykiss (Walbaum), following the injection of a DNA vaccine alone and concurrently with a polyvalent, oil-adjuvanted vaccine.

This research demonstrates a significant increase in routine metabolic rate (RMR) following injection of a DNA vaccine concurrently with a polyvalent, oil-adjuvanted vaccine. The increase in RMR was transient and associated with increased activity of both the non-specific and specific immune responses. Rainbow trout (Oncorhynchus mykiss) were injected with a DNA vaccine (DV), a commercially available polyvalent, oil-adjuvanted vaccine (AV), or the two vaccines in combination and sampled at 203, 305, and 406 days (dd) post-vaccine injection (pvi) for RMR and key immune parameters (serum lysozyme activity, serum neutralization antibody titres). The RMR of fish that received both the DV and the AV was significantly higher at 203 dd pvi, compared to fish from all other treatment groups which included the control, the AV, and the DV groups. The increased RMR corresponded to elevated levels of serum lysozyme activity and an earlier seroconversion of virus-specific neutralizing antibodies. To determine if growth performance was affected by the transient increase in RMR, specific growth rate (SGR), percent daily weight gain (WG), and feed conversion ratio (FCR) were determined at 798, 1204, and 1610 dd pvi. Although fish in all three vaccine groups showed significant increases in SGR and WG at 798 and 1610 dd pvi compared to the control group, the overall weight of the fish was not different at the end of the experiment. In summary, this study shows that concurrent injection of a DV and an AV transiently increases the RMR of rainbow trout and changes the manner in which the immune response occurs, but does not affect the overall growth performance of the fish.

Targeting to static endosome is required for efficient cross-presentation of endoplasmic reticulum-resident oxygen-regulated protein 150-peptide complexes.

Heat shock proteins (HSPs) such as Hsp70, gp96, and Hsp90 have been shown to elicit intriguing, efficient CTL responses by cross-presentation via an as yet entirely unknown mechanism. Oxygen-regulated protein 150 (ORP150), also known as grp170, is an endoplasmic reticulum-resident HSP and is up-regulated by hypoxia. It has been demonstrated that ORP150 binds tumor-associated Ag peptides within cancer cells. Immunization with an ORP150-tumor Ag complex has been shown to generate tumor-specific CTLs. Most recently, it has been shown that exogenous ORP150 induces cross-presentation of a chaperoned Ag, thereby stimulating Ag-specific CTLs. However, the mechanism underlying this efficient cross-presentation is still unsolved. In this study, we show that the ORP150-precursor peptide complex can elicit CTL response through cross-presentation as well as the CD4(+) T cell response by dendritic cells. Furthermore, we observed that the internalized ORP150-peptide complex, but not OVA protein, which was not cross-presented, was sorted to the Rab5(+), EEA1(+) static early endosome, followed by translocation to a recycling endosome, where the ORP150-chaperoned peptide was processed and bound to MHC class I molecules. Moreover, we observed that immunization of mice with ORP150-peptide complexes elicited strong peptide-specific CTLs and antitumor effects in vivo. Our data indicate that targeting of the Ag to a "static" early endosme by ORP150 is required for the efficient cross-presentation.

Exercise-induced elevation in plasma oxidative generating capability augments the temporal inflammatory response stimulated by lipopolysaccharide.

Prolonged oxidative stress is detrimental to health; however, transient oxidative stress may improve immune capability. We examined whether exercise-induced increases in the plasma oxidative generating capability enhance immune responsiveness to potential pathogens. Twelve individuals underwent a 30-min row and pre and post-exercise bloods were collected for oxidative stress and immune assessment. We found that exercise induced a transient increase in plasma carbonyls (3.2-5.3 nmol/mg protein) and creatine kinase activity (0.5-1.2 absorbance/min/mg protein) and that lipopolysaccharide (LPS) stimulation (0.5-24 h) of pre- and post-exercise blood augmented temporal tumour necrosis factor-alpha (TNFalpha) secretion. Further characterisation of plasma using a modified dihydro-2',7'-dichlorohydrofluorescein (DCF) assay revealed that addition of a sub-threshold of hydrogen peroxide to post-exercise (and not pre-exercise) plasma caused a sixfold increase in the radical oxygen species (ROS) generating capability after 15 min (555 +/- 131 to 3607 +/- 488 change in fluorescent intensity [DeltaFI]), which was inhibited using 60 mM N-acetyl-L: -cysteine (920 +/- 154 DeltaFI). Furthermore, cell experiments revealed that LPS stimulation of either THP-1 cells pre-incubated with post-exercise plasma or peripheral blood mononuclear cells pre-treated with pro-oxidants, modulated the temporal secretion of key cytokines that regulate the initiation, progression and resolution of an inflammatory response. These results indicate that exercise-induced changes in plasma parameters (e.g. oxidative generating capability-dependent or independent of inflammatory mediators) augment the temporal LPS response and support the notion that repeated transient oxidative stress (such as that induced by regular exercise) is important for a "healthy" immune system.

Deleterious effects of short-term, high-intensity exercise on immune function: evidence from leucocyte mitochondrial alterations and apoptosis.

BACKGROUND: Although moderate exercise can benefit health, acute and vigorous exercise may have the opposite effect. Strenuous exercise can induce alterations in the physiology and viability of circulating leucocytes, which have a causal relationship with exercise-induced immune distress. OBJECTIVES: To investigate the use of mitochondrial transmembrane potential (MTP), a functional marker of the energy and viability status of leucocytes, for monitoring the immunomodulating effects of short-term, high-intensity exercise. METHODS: 12 healthy volunteers with a mean Vo(2)max of 70.4 ml/kg/min carried out 3 consecutive days of high-intensity exercise (85% of Vo(2)max for 30 min every day). Blood samples were collected at multiple time points immediately before and after each exercise session and at 24 and 72 h after the completion of exercise. Leucocyte MTP, apoptosis and circulatory inflammation markers were measured by flow cytometry and enzyme-linked immunosorbent assays. RESULTS: MTP of peripheral blood leucocytes had declined immediately after the first exercise session and remained subnormal 24 h later. It did not normalise until 72 h after exercise. The sequential changes in MTP were consistent among the three leucocyte subpopulations (polymorphonuclear neutrophils, lymphocytes and monocytes) and were significant (p<0.05). Leucocytes displayed a gradual and incremental change in their propensity for apoptosis during and after exercise. Similarly, plasma concentrations of tumour necrosis factor-alpha and soluble Fas ligand were raised during the exercise sessions and had not normalised by 72 h after the completion of exercise. Correlation between changes in leucocyte MTP and plasma concentrations of tumour necrosis factor-alpha and soluble Fas ligand was variable, but significant for polymorphonuclear neutrophils and lymphocytes (p<0.05). CONCLUSIONS: Short-term, high-intensity exercise can lead to a significant and prolonged dysfunction of the mitochondrial energy status of peripheral blood leucocytes, which is accompanied by an increased propensity for apoptosis and raised pro-inflammatory mediators. These results support the immunosuppressive effects of excessive exercise and suggest that MTP is a useful marker of these effects.

Signal transduction and oxidative processes in sinonasal polyposis.

BACKGROUND: Nasal polyposis is characterized by impaired regulation of nasal tissue growth and is associated with chronic inflammation, sinus infections, and low levels of nitric oxide (NO). Based on its critical role in mediating cell growth and antimicrobial function, decrease of NO levels has been implicated in the pathogenesis of nasal polyposis. OBJECTIVE: We sought to evaluate mechanisms for the low NO level in polyposis, including factors regulating NO synthase (NOS) expression and activity and NO consumptive processes in nasal epithelial cells and nasal lavage fluid. METHODS: Eighteen patients with nasal polyposis and 8 healthy control subjects were studied. Nasal brushings, nasal lavage fluid, and nasal biopsy specimens were collected and analyzed. RESULTS: NO metabolite levels (nitrite and nitrate) in nasal lavage fluid from patients with polyps were less than those in control subjects, but activation of signal transduction and inducer of transcription 1, which regulates inducible NOS gene expression and protein expression, was present at higher levels in polyp than in healthy control tissue. Levels of arginine, methylarginine, and endogenous NOS inhibitors were similar between polyp and control tissue. In contrast, superoxide dismutase activity of polyp tissues was lower than that seen in control tissue and associated with increased nitrotyrosine, a biomarker of oxidant consumptive products of NO. CONCLUSION: Taken together, these data suggest that the nasal polyp environment is characterized by abnormalities in NO metabolism that might predispose to altered regulation of tissue growth and infection. CLINICAL IMPLICATIONS: Identification of NO metabolic abnormalities might lead to novel treatments for sinonasal polyposis targeted against the pathways identified within this study.

The proinflammatory cytokines TNF-alpha and IL-1 beta impair economy of contraction in human myocardium.

Considerable experimental evidence has accumulated over the past years that proinflammatory cytokines, especially TNF-alpha and IL-1beta, impair myocardial function in different animal species. On the other hand, several prospective clinical trials studying TNF-alpha antagonist in patients with chronic heart failure were not able to demonstrate a benefit. As there might be a relevant species-related discrepancy, we intended to prove our previous results demonstrating impaired myocardial economy after exogenous administration of recombinant TNF-alpha in rat myocardium. In the present study, both TNF-alpha and IL-1beta not only revealed an immediate negative inotropic effect but also increased specific oxygen demand in human right-atrial myocardium. Enhanced oxygen consumption was not caused by an elevated basal metabolism but an impaired economy of contraction. Our results suggest that proinflammatory cytokines have a considerable effect on myocardial mechano-energetic parameters in human myocardium as well.

Effects of graded carbohydrate supplementation on the immune response in cycling.

PURPOSE: This study examined the acute immune response after three standardized cycling sessions of 4-h duration in the field with varying carbohydrate (CHO) supplementation in a randomized, double-blind, placebo-controlled fashion. We hypothesized that the ingestion of carbohydrate (6 or 12% CHO beverages; placebo (P) without CHO) during exercise attenuates the exercise-induced immune response in a dose-dependent manner. METHODS: A total of 14 male competitive cyclists and triathletes (age: 25 +/- 5 yr; height: 180 +/- 7 cm; weight: 72 +/- 9 kg; VO2max: 67 +/- 6 mL.min(-1).kg(-1)) cycled for 4 h on a 400-m track at a given workload of 70% of the individual anaerobic threshold (198 +/- 21 W). Leukocyte and lymphocyte subpopulations were measured by flow cytometry before, immediately, and 1 and 19 h after exercise. In addition, C-reactive protein (CRP) interleukin 6 (IL-6), and cortisol were determined. RESULTS: The exercise-induced increase in leukocytes, neutrophils, and monocytes was significantly attenuated to the same extent by 6 and 12% CHO (P < 0.001). No differences could be demonstrated for lymphocytes and natural killer cells. The increase in CRP was attenuated significantly by 12% CHO only (P < 0.05), whereas the increase in cortisol and IL-6 was significantly reduced by 6 and 12% CHO (P < 0.001). The postexercise neutrophilia, which dominated the exercise-induced leukocytosis, was strongly related to the postexercise concentration of cortisol (r = 0.72; P < 0.001). CONCLUSIONS: Because of the lacking dose-dependent difference, the ingestion of at least 6% CHO beverages can sufficiently attenuate the exercise-induced immune response and stress, especially in phagocytizing cells (neutrophils and monocytes) by the reduced release of cortisol.