Increased Plasma IL-6 Research Articles

Abstract 155: Identification of Decreased Plasma Lysophosphatidylcholine Using Phospholipidomics in Cardiac Arrest: A Novel Therapeutic Application

Introduction: Cardiac arrest (CA) is a significant public health burden with few effective therapies available. Plasma phospholipids are important for proper organ function. We hypothesized that alterations in plasma phospholipids may play an important role in the pathophysiology of CA and normalizing these alterations may be a novel therapeutic application for the treatment of CA. Objective: The aim of this study was to test the phospholipid therapy as a novel therapeutic approach in CA. Methods and Results: We performed phospholipidomics on plasma samples from CA patients and controls from North Shore University Hospital to identify plasma phospholipids that correlate with injury severity. We then confirmed the finding using our rat model of 10 and 14 min of asphyxia-induced CA. Finally, we tested the effect of administering LPC using the same model. From the phospholipids analyzed, lysophosphatidylcholine (LPC) levels were found to be the most significantly decreased in CA patients, which was also associated with survival of patients. The same trend was observed in the rat model where rats after 14 min CA had significantly lower plasma LPC levels than rats after 10 min CA. We also found that LPC levels began to decrease continuously following resuscitation, but not during the ischemic phase of CA. Finally, we found that LPC administration substantially increased rat survival compared to the control group. Rats who survived in the LPC-treated group displayed significantly improved brain function and the neuroprotective effect of LPC is supported by improved brain histology. We also found LPC treatment increased plasma IL-10 levels and decreased IL-6 levels post-CA. Conclusion: Plasma LPC levels inversely correlated with survival and LPC treatment significantly improved brain function and rat survival. This data indicates that the decrease of plasma LPC is a major mechanism responsible for brain damage demonstrating the potential of LPC as a novel therapeutic in CA.

Abstract 140: Effects of ω-3 Polyunsaturated Fatty Acids on Systemic Inflammation and Post-resuscitation Myocardial Function in a Rat Model of Cardiac Arrest and Cardiopulmonary Resuscitation

Introduction: Massive systemic inflammation is a primary cause of myocardial dysfunction following cardiac arrest (CA) and resuscitation (CPR). We investigated the effects of ω-3 polyunsaturated fatty acids (ω-3 PUFA) on systemic inflammation and myocardial function after CA and CPR. Hypothesis: Administration of ω-3 PUFA at the start of CPR will alleviate post CPR inflammation and improve cardiac function in a rat model of CA and CPR. Methods: 18 male Sprague-Dawley rats weighing between 450g-550g were randomized into three groups: Sham, Control, and ω-3 PUFA. Ventricular fibrillation (VF) was induced and untreated for 6 min. 4J defibrillation was attempted after 8 min of CPR. Saline placebo or ω-3 PUFA (5mL/kg) was infused at the start of CPR and continued for 4h. Ejection fraction (EF), cardiac output (CO) and myocardial performance index (MPI) were measured by echocardiography at baseline, 1, 3 and 6h after return of spontaneous circulation (ROSC). Inflammatory cytokines (IL-6 and TNF-α) and cardiac biomarker (cTnI) levels in plasma were detected at baseline and 6 hrs after ROSC. Results: A decrease in EF and CO and an increase in MPI occurred after resuscitation. Significant improvement was noted in ω-3 PUFA compared to control animals (p<0.05) (Fig. 1). ELISA analysis showed increased plasma IL-6, TNF-α, and cTnI in post-resuscitated rats. Administration of ω-3 PUFA attenuated the rise in these plasma biomarkers (p<0.05) (Fig. 2). Conclusion: Administration of ω-3 PUFA attenuates post-resuscitation systemic inflammation and improves myocardial function in a rat model of CA and CPR.

Levels and Clinical Significance of Regulatory B Cells and T Cells in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy, whose immunological mechanisms are still partially uncovered. Regulatory B cells (Bregs) and CD4+ regulatory T cells (Tregs) are subgroups of immunoregulatory cells involved in modulating autoimmunity, inflammation, and transplantation reactions. Herein, by studying the number and function of Breg and Treg cell subsets in patients with AML, we explored their potential role in the pathogenesis of AML. Newly diagnosed AML patients, AML patients in complete remission, and healthy controls were enrolled. Flow cytometry was used to detect percentages of Bregs and Tregs. ELISA was conducted to detect IL-10 and TGF-β in plasma. The mRNA levels of IL-10 and Foxp3 were measured with RT-qPCR. The relationship of Bregs and Tregs with the clinicopathological parameters was analyzed. There was a significant reduction in the frequencies of Bregs and an increase of Tregs in newly diagnosed AML patients compared with healthy controls. Meanwhile, patients in complete remission exhibited levels of Bregs and Tregs comparable to healthy controls. Furthermore, compared with healthy controls and AML patients in complete remission, newly diagnosed AML patients had increased plasma IL-10 but reduced TGF-β. IL-10 and Foxp3 mRNA levels were upregulated in the newly diagnosed AML patients. However, there were no significant differences in IL-10 and Foxp3 mRNA levels between patients in complete remission and healthy controls. Bregs and Tregs have abnormal distribution in AML patients, suggesting that they might play an important role in regulating immune responses in AML.

Cytokine status in patients with myocardial infarction as a possible predictor of coronary atherosclerosis severity

Aim. To study the association of cytokine status with coronary atherosclerosis severity in patients with myocardial infarction (MI).Material and methods. Between 11.2018 and 07.2019, 92 patients hospitalized with MI in Perm Clinical Cardiology Dispensary were included in the study. The control group consisted of 23 patients with stable coronary artery disease. In addition to the standard examination, enzyme-linked immunosorbent assay was used to determine the levels of interleukins (IL)-6, -10, tumor necrosis factor alpha (TNF-α), C-reactive protein.Results. Significant increase in plasma IL-6, TNF-α and C-reactive protein levels in MI patients compared with the control group. The increase in the concentration of IL-6, TNF-α, as well as the IL-6/IL-10 ratio occurs in proportion to coronary atherosclerosis severity. A direct correlation of Gensini score with IL-6, TNF-α, and IL-6/IL-10 ratio was established.Conclusion. Further study of cytokine profile parameters in MI patients will help a clearer understanding pathogenesis of coronary artery atherosclerosis. An increase in concentrations of IL-6, TNF-α, and IL-6/IL-10 ratio is associated with an increase in coronary atherosclerosis severity and can be used in practice for its prediction.

Interleukin-10 and non-classical monocytes as biomarkers of ischemic cardiomyopathy

Background. Chronic heart failure frequently occurs against the background of ischemic heart disease (IHD), and has also been associated with the diagnosis of ischemic cardiomyopathy (ICMP). While there are significant commonalities with respect to underlying mechanisms, it would be most important to identify differential diagnostic markers to facilitate diagnosis and verification at the early stages of disease.Aim. The intent of this study was to perform a quantitative assessment of non-classical monocytes in patients diagnosed with IHD with or without ICMP and to identify any relationships between non-classical monocytes and plasma concentrations of proinflammatory (interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α) and anti-inflammatory (IL-4, IL-10, IL-13) cytokines.Methods. We examined 44 patients diagnosed with IHD, aged 49 - 63 years, with class II-III heart failure as per the New York Heart Association criteria. Of this group, 18 were also diagnosed with ICMP. The comparison group included 14 age-matched healthy controls. Percentages of non-classical (CD14+CD16+) monocytes in peripheral blood were determined by flow cytometry and the concentrations of IL-1β, IL-4, IL-6, IL-10, IL-13 and TNF-α were measured by enzyme-linked immunosorbent assay.Results. Amongst the patients diagnosed with ICMP, the concentration of IL-10 in blood plasma was higher than in those without this diagnosis, detected at 30.05 pg/ml (range 24.75 - 33.50 pg/ml, р=0.0412); the percentage of non-classical monocytes was lower, at 5.05% (range 4.08 - 6.58%, р=0.0094). Amongst patients diagnosed with IHD without ICMP, these parameters were within normal limits. The plasma concentrations of IL-1β, IL-6 and IL-13 in both groups were comparable to values obtained from healthy donors and IL-4 was undetectable throughout. Amongst patients diagnosed with ICMP, plasma TNF-α was detected at elevated levels that were comparable to those determined for patients diagnosed with IHD without ICMP.Conclusion. Imbalance of cytokines in blood in patients with coronary artery disease is characterized by excess TNF-α, absence of IL-4, and normal levels of IL-1β, IL-6 and IL-13, regardless of the type of ischemic myocardial injury. In patients with ICMP, we detected an overall decrease in the fraction of non-classical monocytes in association with an increase in plasma IL-10; these features were not detected in patients diagnosed with IHD without ICMP. As such, these biological responses may be used for timely diagnosis of ICMP. Received 27 May 2019. Revised 7 October 2019. Accepted 30 October 2019. Funding: The work is supported by grants of the Russian Foundation for Basic Research No. 18-015-00160\19 and the President of the Russian Federation No. НШ-2690.2018.7 and No. МД-2788.2019.7. Conflict of interest: Authors declare no conflict of interest. Author contributionsConception and study design: V.M. Shipulin, S.P. ChumakovaData collection and analysis: V.M. Shipulin, S.P. Chumakova, O.I. Urazova, M.V. Vins, V.V. NovickiyLiterature review: S.P. Chumakova, D.A. Pogonchenkova, A.S. PryakhinDrafting the article: S.P. Chumakova, D.A. Pogonchenkova, O.I. UrazovaCritical revision of the article: V.M. Shipulin, V.V. NovickiyStatistical analysis: S.P. ChumakovaFinal approval of the version to be published: V.M. Shipulin, S.P. Chumakova, D.A. Pogonchenkova, O.I. Urazova, M.V. Vins, A.S. Pryakhin, V.V. Novickiy

Daily Consumption of an Anthocyanin-Rich Extract Made From New Zealand Blackcurrants for 5 Weeks Supports Exercise Recovery Through the Management of Oxidative Stress and Inflammation: A Randomized Placebo Controlled Pilot Study.

Background: Regular exercise is essential to a healthy lifestyle but evokes an oxidative and inflammatory stress. Depending upon its intensity and duration this can result in either beneficial adaptive changes or underlying tissue damage that impacts upon long-term health and individual sporting training schedules. Functional foods containing plant bioactives have potential to support exercise through management of the detrimental aspects of exercise and complement ergonomic adaptive benefits.Aim: Previously we reported that a single consumption of a 3.2 mg/kg New Zealand blackcurrant anthocyanin-rich extract (BAE) 1 h before a 30 min rowing exercise attenuated moderate exercise-mediated oxidative stress and supported innate immunity. Here we evaluate whether the efficacy of a single consumption of BAE 1 h prior to exercise is changed after extended daily BAE consumption for 5 weeks.Results: On week 1, a single consumption of BAE 1 h before a 30 min row mediated a significant (p < 0.05) 46% reduction in post-exercise-induced malondialdehyde (MDA) by 2 h compared to a 30% reduction in the placebo group. Similar efficacy was observed 5 weeks later after daily consumption of BAE. In addition, daily BAE consumption for 5 weeks improved the efficacy to (a) resolve acute inflammation, and (b) increased plasma IL-10, salivary beta-defensin 2 (BD2) and secretory IgA. Although no change in plasma antioxidant capacity was detected, a significant (p < 0.009) positive correlation between plasma IL-10 and plasma antioxidant capacity (R2 = 0.35) was observed on week 6 after 5 week BAE consumption suggesting IL-10 influences antioxidant properties. Using a differentiated myotubule cell-line revealed that whilst IL-10 had no direct antioxidant neutralizing action, longer-term exposure (24 h) attenuated 2,2′-Azobis(2-amidinopropane) dihydrochloride (AAPH)-induced myotubule oxidative stress, supporting a putative role for IL-10 in the modulation of cellular antioxidant systems.Conclusions: Daily consumption of BAE for 5 weeks serves to enhance the exercise recovery effectiveness of a single consumption of BAE and promotes beneficial/protective antioxidant/anti-inflammatory cellular events that facilitate exercise recovery.

Pancreatic secretory trypsin inhibitor reduces multi-organ injury caused by gut ischemia/reperfusion in mice.

Intestinal ischemia/reperfusion (I/R) injury occurs during transplantation, mesenteric arterial occlusion, trauma and shock, causing systemic inflammation, multiple organ dysfunction and high mortality. Pancreatic secretory trypsin inhibitor (PSTI), a serine protease inhibitor expressed in gut mucosa may function as a mucosal protective/repair peptide. We examined whether PSTI affected mesenteric I/R-induced injury. Hypoxia/normoxia (H/N) caused 50% drop in cell viability of AGS, RIE1 and Caco-2 cells but PSTI (10 μg/ml) given prior- or during-hypoxic period improved survival by 50% (p<0.01). Similarly, Caco-2 monolayers exposed to H/N had 300% increase in transepithelial permeability, PSTI truncated this by 50% (p<0.01). Mice underwent mesenteric I/R by clamping jejunum, causing severe mucosal injury, increased apoptotic markers and 3-fold increases in plasma IL-6, IL1β, TNFα, and tissue lipid peroxidation (MDA) and inflammatory infiltration (MPO) levels. Lungs showed similar significant injury and inflammatory infiltrate markers. Smaller increases in MDA and MPO were seen in kidney & liver. PSTI (20 mg/kg) reduced all injury markers by 50–80% (p<0.01). In vitro and in vivo studies showed PSTI reduced pro-apoptotic Caspase 3, 9 and Baxα levels, normalised Bcl2 and caused additional increases in HIF1α, VEGF and Hsp70 above rises caused by I/R alone (all p<0.01). PSTI also prevented reduction of tight junction molecules ZO1 and Claudin1 (all p<0.01) but did not affect increased ICAM-1 caused by I/R in gut or lung. PSTI may be a useful clinical target to prevent I/R injury.

IL-6-mediated hepatocyte production is the primary source of plasma and urine neutrophil gelatinase–associated lipocalin during acute kidney injury

Neutrophil gelatinase associated lipocalin (NGAL, Lcn2) is the most widely studied biomarker of acute kidney injury (AKI). Previous studies have demonstrated that NGAL is produced by the kidney and released into the urine and plasma. Consequently, NGAL is currently considered a tubule specific injury marker of AKI. However, the utility of NGAL to predict AKI has been variable suggesting that other mechanisms of production are present. IL-6 is a proinflammatory cytokine increased in plasma by two hours of AKI and mediates distant organ effects. Herein, we investigated the role of IL-6 in renal and extra-renal NGAL production. Wild type mice with ischemic AKI had increased plasma IL-6, increased hepatic NGAL mRNA, increased plasma NGAL, and increased urine NGAL; all reduced in IL-6 knockout mice. Intravenous IL-6 in normal mice increased hepatic NGAL mRNA, plasma NGAL and urine NGAL. In mice with hepatocyte specific NGAL deletion (Lcn2hep-/-) and ischemic AKI, hepatic NGAL mRNA was absent, and plasma and urine NGAL were reduced. Since urine NGAL levels appear to be dependent on plasma levels, the renal handling of circulating NGAL was examined using recombinant human NGAL. After intravenous recombinant human NGAL administration to mice, human NGAL in mouse urine was detected by ELISA during proximal tubular dysfunction, but not in pre-renal azotemia. Thus, during AKI, IL-6 mediates hepatic NGAL production, hepatocytes are the primary source of plasma and urine NGAL, and plasma NGAL appears in the urine during proximal tubule dysfunction. Hence, our data change the paradigm by which NGAL should be interpreted as a biomarker of AKI.

Inflammation and kynurenine pathway dysregulation in post-partum women with severe and suicidal depression

Depression during pregnancy and the post-partum is common, with severe cases resulting in suicidal behavior. Despite the urgent and unmet medical need, the biological underpinnings of peri-partum depression remain unclear. It has been suggested that it is triggered by dynamic changes of the immune system during pregnancy and at delivery. Therefore, we investigated whether a pro-inflammatory status in plasma, together with changes in the kynurenine pathway activity, is associated with the development of severe depression and suicidal behavior in the post-partum. Our cross-sectional study targets a unique, understudied population in which the pronounced severity of symptoms required hospitalization.We analyzed plasma IL-1β, IL-2, IL-6, IL-8, TNF-α, tryptophan, serotonin, kynurenine, nicotinamide, quinolinic- and kynurenic acids in post-partum women diagnosed with peripartum onset depression (PPD) and healthy controls (n = 165). We assessed depression severity using the Edinburgh Postnatal Depression Scale and suicidality using the Columbia-Suicide Severity Rating Scale.We found that increased plasma IL-6 and IL-8 and reductions of serotonin, IL-2 and quinolinic acid were associated with the severity of depressive symptoms and increased the risk for PPD. Moreover, women with lower serotonin levels were at an increased risk for suicidal behavior, even when adjusting for depression severity, psychosocial factors, age BMI, and medication.Our results indicate that severe depression in the post-partum involves dysregulation of the immune response and the kynurenine pathway, with a concomitant reduction in serotonin levels. We propose that inflammatory cytokines and the kynurenine pathway are potential treatment targets in PPD, opening up the possibility of novel therapeutic strategies targeting the peripartum.

Probucol-poly(meth)acrylate-bile acid nanoparticles increase IL-10, and primary bile acids in prediabetic mice.

Aim: Common features in insulin-resistance diabetes include inflammation and liver damage due to bile acid accumulation. Results &methodology: This study aimed to test in vivo pharmacological effects of combining two drugs, ursodeoxycholic acid that has bile acid regulatory effects, and probucol (PB) that has potent anti-oxidative stress effects, using a new poly(meth)acrylate nano-targeting formulation on prediabetic mice. Mice were made diabetic and were fed daily with either PB, nanoencapsulated PB or nanoencapsulated PB-ursodeoxycholic acid before blood, tissues, urine and feces were collected for inflammation and bile acid measurements. The nanoencapsulated PB-ursodeoxycholic acid formulation increased plasma IL-10, and increased the concentration of primary bile acids in the liver and heart. Conclusion: Results suggest potential applications in regulating IL-10in insulin-resistance prediabetes.

Peripheral Administration of IL-13 Induces Anti-inflammatory Microglial/Macrophage Responses and Provides Neuroprotection in Ischemic Stroke

Neuroinflammation is strongly induced by cerebral ischemia. The early phase after the onset of ischemic stroke is characterized by acute neuronal injury, microglial activation, and subsequent infiltration of blood-derived inflammatory cells, including macrophages. Therefore, modulation of the microglial/macrophage responses has increasingly gained interest as a potential therapeutic approach for the ischemic stroke. In our study, we investigated the effects of peripherally administered interleukin 13 (IL-13) in a mouse model of permanent middle cerebral artery occlusion (pMCAo). Systemic administration of IL-13 immediately after the ischemic insult significantly reduced the lesion volume, alleviated the infiltration of CD45+ leukocytes, and promoted the microglia/macrophage alternative activation within the ischemic region, as determined by arginase 1 (Arg1) immunoreactivity at 3 days post-ischemia (dpi). Moreover, IL-13 enhanced the expression of M2a alternative activation markers Arg1 and Ym1 in the peri-ischemic (PI) area, as well as increased plasma IL-6 and IL-10 levels at 3 dpi. Furthermore, IL-13 treatment ameliorated gait disturbances at day 7 and 14 and sensorimotor deficits at day 14 post-ischemia, as analyzed by the CatWalk gait analysis system and adhesive removal test, respectively. Finally, IL-13 treatment decreased neuronal cell death in a coculture model of neuroinflammation with RAW 264.7 macrophages. Taken together, delivery of IL-13 enhances microglial/macrophage anti-inflammatory responses in vivo and in vitro, decreases ischemia-induced brain cell death, and improves sensory and motor functions in the pMCAo mouse model of cerebral ischemia.

A comparison of effects of scalp nerve block and local anesthetic infiltration on inflammatory response, hemodynamic response, and postoperative pain in patients undergoing craniotomy for cerebral aneurysms: a randomized controlled trial

BackgroundThe purpose of this study was to compare the effects of scalp nerve block (SNB) and local anesthetic infiltration (LA) with 0.75% ropivacaine on postoperative inflammatory response, intraoperative hemodynamic response, and postoperative pain control in patients undergoing craniotomy.MethodsFifty-seven patients were admitted for elective craniotomy for surgical clipping of a cerebral aneurysm. They were randomly divided into three groups: Group S (SNB with 15 mL of 0.75% ropivacaine), group I (LA with 15 mL of 0.75% ropivacaine) and group C (that only received routine intravenous analgesia). Pro-inflammatory cytokine levels in plasma for 72 h postoperatively, hemodynamic response to skin incision, and postoperative pain intensity were measured.ResultsThe SNB with 0.75% ropivacaine not only decreased IL-6 levels in plasma 6 h after craniotomy but also decreased plasma CRP levels and increased plasma IL-10 levels 12 and 24 h after surgery compared to LA and routine analgesia. There were significant increases in mean arterial pressure 2 and 5 mins after the incision and during dura opening in Groups I and C compared with Group S. Group S had lower postoperative pain intensity, longer duration before the first dose of oxycodone, less consumption of oxycodone and lower incidence of PONV through 48 h postoperatively than Groups I and C.ConclusionPreoperative SNB attenuated inflammatory response to craniotomy for cerebral aneurysms, blunted the hemodynamic response to scalp incision, and controlled postoperative pain better than LA or routine analgesia.Trial registrationClinicaltrials.gov NCT03073889 (PI:Xi Yang; date of registration:08/03/2017).

The effect of resistance exercise upon age-related systemic and local skeletal muscle inflammation.

Chronic inflammation increases with age and is correlated positively to visceral fat mass, but inversely to muscle mass. We investigated the hypothesis that resistance training would increase muscle mass and strength together with a concomitant drop in local and systemic inflammation level independent of any changes in visceral fat tissue in elderly. 25 subjects (mean 67, range 62-70 years) were randomized to 1 year of heavy resistance training (HRT) or control (CON), and tested at 0, 4 and 12 months for physical performance, body composition (DXA), vastus lateralis muscle area (MRI) local and systemic inflammation (blood and muscle). In addition, systemic and local muscle immunological responses to acute exercise was determined before and after the training period. Increases in muscle mass (≈2%, p < 0.05), vastus lateralis area (≈9%. P < 0.05), isometric (≈15%) and dynamic (≈15%) muscle strength (p < 0.05) were found in the HRT group after 12 months training. HRT did not alter overall or visceral fat mass (p > 0.05). Blood C-Reactive Protein declined over time in both groups (p < 0.05), whereas muscle inflammation markers were unchanged to 1 year of HRT. Acute exercise increased plasma IL-6 and FGF-19 (p < 0.05), decreased FGF-21 (p < 0.05) and CCL-20 (p < 0.05), and increased GDNF in muscle (p < 0.001) similarly before and after 1 year in both groups. Long term resistance training increased muscle strength and improved muscle mass, but did not alter visceral fat mass and did not show any specific effect upon resting or exercise induced markers of inflammation.

Involvement of IL-6 and GSK3β in impaired sensorimotor gating induced by high-fat diet

Increased levels of proinflammatory cytokines have been implicated in schizophrenia; however, their pathophysiological roles in abnormal brain dysfunctions remain unclear. We evaluated the effect of proinflammatory cytokines on a high-fat diet (HFD)-induced prepulse inhibition (PPI) deficits in the acoustic startle response. Eight-week-old male C57BL/6J mice were fed a HFD for 3 weeks and then PPI was examined. HFD significantly induced PPI deficits and increased plasma IL-6, but not TNFα, levels. Interestingly, MR16-1 administration during the HFD period ameliorated PPI deficits. Further, in the striatum of HFD-fed mice, phosphorylation of GSK3β, but not GSK3α, was significantly increased; this increase was attenuated by MR16-1, although the protein levels of GSK3α and β were not altered. There were no significant differences in either phosphorylation or protein levels of GSK3α, β in the PFC during the HFD period. These results suggest that increased IL-6 levels during HFD may induce sensorimotor gating deficits, likely through the alteration of striatal GSK3β phosphorylation. MR16-1 might have a beneficial effect on such HFD-induced sensorimotor gating deficits.

Molecular hydrogen potentiates hypothermia and prevents hypotension and fever in LPS-induced systemic inflammation

Molecular hydrogen (H2) exerts anti-oxidative, anti-apoptotic, and anti-inflammatory effects. Here we tested the hypothesis that H2 modulates cardiovascular, inflammatory, and thermoregulatory changes in systemic inflammation (SI) induced by lipopolysaccharide (LPS) at different doses (0.1 or 1.5 mg/kg, intravenously, to induce mild or severe SI) in male Wistar rats (250–300 g). LPS or saline was injected immediately before the beginning of 360-minute inhalation of H2 (2% H2, 21% O2, balanced with nitrogen) or room air (21% O2, balanced with nitrogen). Deep body temperature (Tb) was measured by dataloggers pre-implanted in the peritoneal cavity. H2 caused no change in cardiovascular, inflammatory parameters, and Tb of control rats (treated with saline). During mild SI, H2 reduced plasma surges of proinflammatory cytokines (TNF-α and IL-6) while caused an increase in plasma IL-10 (anti-inflammatory cytokine) and prevented fever. During severe SI, H2 potentiated hypothermia, and prevented fever and hypotension, which coincided with reduced plasma nitric oxide (NO) production. Moreover, H2 caused a reduction in surges of proinflammatory cytokines (plasma TNF-α and IL-1β) and prostaglandin E2 [(PGE2), in plasma and hypothalamus], and an increase in plasma IL-10. These data are consistent with the notion that H2 blunts fever in mild SI, and during severe SI potentiates hypothermia, prevents hypotension reducing plasma NO production, and exerts anti-inflammatory effects strong enough to prevent fever by altering febrigenic signaling and ultimately down-modulating hypothalamic PGE2 production.

Prophylactic vs. Therapeutic Treatment With P2Et Polyphenol-Rich Extract Has Opposite Effects on Tumor Growth.

Polyphenols have tumoricidal effects via anti-proliferative, anti-angiogenic and cytotoxic mechanisms and have recently been demonstrated to modulate the immune response through their anti- or pro- oxidant activity. Nevertheless, it remains controversial whether antioxidant-rich supplements have real beneficial effects on health, especially in complex diseases such as cancer. We previously identified a polyphenol-rich extract obtained from Caesalpinia spinosa (P2Et) with anti-tumor activity in both breast carcinoma and melanoma. The present work evaluated the ability of P2Et extract to modulate the immune system in either the steady state or following tumor challenge. We found that the prophylactic treatment of healthy mice increased the number of CD4+ and CD8+ activated T, NK, regulatory T, dendritic and myeloid-derived suppressor cells in lymphoid organs together with a significant increase in plasma IL-6. Interestingly, this pre-conditioning of the host immune system with P2Et did not involve a protective effect against the control of tumor growth and metastasis in transplantable models of melanoma (B16) and breast cancer (4T1), but in contrast, a detrimental effect was observed in both models. We further demonstrated that this effect was at least partly due to an increase in regulatory T cells, myeloid-derived suppressor cells, and proinflammatory cytokines, with a concomitant decrease in CD4+ and CD8+ T cells. Taken together, these results suggest that the anti-tumor and immunomodulation properties of the P2Et extract critically depend on the presence of the tumor and might be mediated by the complex interactions between the tumor cells and the other components of the tumor microenvironment.

Acute Effects of Whole-Body Vibration on Inflammatory Markers in People with Chronic Obstructive Pulmonary Disease: A Pilot Study.

Whole-body vibration (WBV) has gained prominence in the rehabilitation of individuals with chronic obstructive pulmonary disease (COPD) because it is a safe and low intensity exercise that promises beneficial effects on physical performance and quality of life. However, its effects on plasma cytokine levels in COPD are still unclear. The aim of the current study was to investigate the acute effects of WBV on inflammatory biomarkers in people with COPD. Twenty-six participants, COPD people (n=13) and healthy controls (n=13), were included. Both groups performed WBV at amplitude of 2 mm and frequency of vibration of 35 Hz, during six series of 30 seconds. They were assessed for lung function, body composition, 6-minute walking test (6MWT), handgrip strength test, plasma concentrations of interleukin (IL), IL-6, IL-8, and IL-10, and soluble tumor necrosis factor alpha (TNF-α) receptors (sTNFR-1 and sTNFR-2). People with COPD had moderate disease [forced expiratory volume in the first second (FEV1) = 58.1%], as well as a worse performance in the 6MWT. The plasma cytokine profile at rest showed that participants with COPD had higher levels of IL-8 and lower levels of IL-10. After one session of WBV, we found an increased plasma IL-10 level in the COPD group, with similar levels for healthy controls. One session of WBV modified the plasma IL-10 level. No effects were found on the other investigated cytokines.

Expression and significance of peripheral myeloid-derived suppressor cells in chronic hepatitis B patients

BackgroundMyeloid-derived suppressor cells (MDSCs) exert their suppressive effects on multiple immune response and contribute to the development of many diseases. However, limited data is available on the involvement of MDSCs in human chronic HBV infection. ObjectiveTo investigate whether the progression of chronic HBV infection was associated with imbalance of MDSCs. MethodsThe percentages of MDSCs, regulatory T (Treg), Th1 and Tc1 cells in the peripheral blood from chronic hepatitis B (CHB) patients and healthy controls (HC) were determined by flow cytometry. Plasma levels of IL-10, TGF-β and IFN-γ were measured using enzyme-linked immunosorbent assay. The potential association of the frequencies of MDSCs with clinical parameters was assessed. ResultsThe percentages of MDSCs and Treg cells were significantly higher in CHB patients than those in HC. The percentages of MDSCs were negatively correlated with Th1 cells. Increased plasma IL-10 level and decreased IFN-γ level were found in CHB patients compared with HC. Moreover, the frequencies of MDSCs and plasma IL-10 levels were positively correlated with serum HBV DNA loads, as well as liver function impairment. ConclusionThe expanded peripheral MDSCs may contribute to poor viral clearance and disease progression during chronic HBV infection.

Intrinsic anti‐inflammatory properties of serum in deep‐diving seals

Diving seals are repeatedly exposed to hypoxia‐reoxygenation and other pro‐inflammatory stimuli such as shear stresses in alveoli from lung collapse and re‐expansion. Moreover, they have a known hyperlipidemic status, which is associated with vascular inflammatory stress in humans and mice. To investigate potential protective strategies in free‐living populations of deep‐diving seals, we examined baseline levels of cytokine biomarkers, as well as the inflammatory response of IL6 gene expression in seal blood cells exposed to an endotoxin (LPS, lipopolysaccharide, 1–1000ng/mL). Despite aspects of their basic physiology that predisposes other mammals to inflammatory stress, cytokine production in healthy Weddell seals (adults and pups) and Northern elephant seals (adults only) following LPS incubation was blunted (10–100X increase in plasma IL6), compared to human samples assayed under the same conditions (&gt;1000X increase). These plasma samples, further assayed using a cytokine panel validated for pinnipeds, revealed that many cytokines were below detectable levels in Weddell seals, with only IL6, IL10 and TNFα exhibiting a dose‐response to LPS. Under isolated, in vitro conditions, Weddell seal monocytes maintained the expected, robust response to stimulation with LPS endotoxin. However, when this response was compared under typical cell culture conditions (using media supplemented with FBS) versus media supplemented with an equivalent amount of Weddell seal serum (WSS), IL6 expression from stimulated monocytes exposed to WSS declined significantly (LPS dose*serum‐type 2way repeated‐measures ANOVA across all doses: F1,6= 8.5, p=0.027 for FBS vs WSS), as did cytokines detected in the cell culture media. To further elucidate the potential anti‐inflammatory properties of seal serum, we repeated the experiment comparing FBS to de‐complemented WSS in RAW cells, a mouse macrophage line. These results validated our findings from seal monocytes, demonstrating that mouse cytokine expression (IL6, TNFα, and Mcp1), was consistently reduced in cells cultured with WSS compared to FBS. Finally, we confirmed that these results held in RAW cells exposed to other TLR ligands, including Pam‐3‐Cys, Poly I:C and CpG DNA (TNFα expression in WSS&lt;FBS, p=0.0001 in each experiment). These findings suggest that seal serum innately possesses anti‐inflammatory properties, which may protect these deep divers from naturally occurring inflammatory challenges such as dive‐induced hypoxia‐reoxygenation and lung collapse.Support or Funding InformationFunded by the National Science Foundation (Office of Polar Programs).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of Vitamin C to The Plasma Level of Interleukin-6, Plasma MDA and Length of Hospitalization of COPD Exacerbation Patient

Background: Exacerbation is an acute condition characterized by worsening of symptoms that require a change in therapy. Increased inflammation of the airways and lungs during exacerbations causes an increase in plasma IL-6 and MDA levels and causes most patients needed treatment at the hospital. Vitamin C is an antioxidant vitamin that has anti-inflammatory and antioxidant effects so that it can be added to COPD exacerbations therapy. This study aims to determine the effect of vitamin C on plasma IL-6, plasma MDA levels and length of hospitalization of acute exacerbation of COPD patients.&#x0D; Methods: This research is an experimental study with pre-test and post-test design. Subjects consisted of 33 patients with exacerbation of COPD were treated at the Soehadi Pridjonegoro Hospital Sragen in October-November 2015 which were selected by purposive sampling. Subjects were divided into two groups, the treatment group (n=16) received vitamin C therapy 1x1000 mg/day and the control group (n=17) received 5 mL of NaCl 0.9%. Levels of IL-6 plasma and plasma MDA was measured on admission and at discharge criteria are met. Length of hospitalization is calculated based on the number of days’ patients in hospital.&#x0D; Results: There was no statistically significant difference to decreased of IL-6 plasma level (P=0.379), MDA plasma level (P=0.27) and length of hospitalization (P=0.24) between treatment and control group. &#x0D; Conclucions: The addition of vitamin C 1x1000 mg/day during hospitalization is not helpful to decreased in levels of plasma IL-6, plasma MDA and length of hospitalization in this study. (J Respir Indo 2018; 38(1): 24-32)