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Neuromuscular electrical stimulation and protein during bed rest increases CD11b+ skeletal muscle macrophages but does not correspond to muscle size or insulin sensitivity.
Reidy, PT, Edvalson, LT, McKenzie, AI, Petrocelli, JJ, Mahmassani, ZS, Drummond, MJ
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2020;(11):1261-1269
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Abstract
With this cohort, we previously demonstrated preservation of thigh lean tissue with neuromuscular electrical stimulation combined with protein supplementation (NMES+PRO) treatment during bed rest in healthy older adults. Because macrophage polarization plays a significant role in the repair and maintenance of muscle size and insulin sensitivity, we hypothesized that muscle macrophages would be induced by NMES+PRO and would correspond to an increase in lean mass and an attenuated insulin resistance response altered by bed rest. Older adults (60-80 years old; body mass index < 30 kg/m2) underwent 5 days of bed rest and were randomized to either thrice daily treatment of NMES+PRO (n = 8) or CON (n = 8). Lean mass, insulin sensitivity, and markers of muscle macrophages, inflammation, and connective tissue were determined before and after bed rest. Glucose intolerance and insulin resistance occurred after bed rest but there was not a treatment effect (p > 0.10). Proinflammatory-like macrophages (CD11b+, CD206-) increased (p < 0.05) with NMES+PRO treatment and was different than CON. Minor changes in noncontractile tissue were observed. However, changes in muscle macrophages or extracellular matrix were not related to the preservation of thigh lean mass or insulin resistance. Daily NMES+PRO treatment during bed rest induced a muscle proinflammatory-like macrophage response and was unrelated to muscle size or metabolic function. This study is listed as clinical trial NCT02566590. Novelty Neuromuscular electrical stimulation combined with protein supplementation (NMES+PRO) increased proinflammatory-like macrophages and extracellular matrix content in older adults after bed rest. NMES+PRO changes in macrophages and noncontractile tissue macrophages were not related to muscle size preservation or insulin sensitivity.
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Blood flow restricted training leads to myocellular macrophage infiltration and upregulation of heat shock proteins, but no apparent muscle damage.
Nielsen, JL, Aagaard, P, Prokhorova, TA, Nygaard, T, Bech, RD, Suetta, C, Frandsen, U
The Journal of physiology. 2017;(14):4857-4873
Abstract
KEY POINTS Muscular contractions performed using a combination of low external loads and partial restriction of limb blood flow appear to induce substantial gains in muscle strength and muscle mass. This exercise regime may initially induce muscular stress and damage; however, the effects of a period of blood flow restricted training on these parameters remain largely unknown. The present study shows that short-term, high-frequency, low-load muscle training performed with partial blood flow restriction does not induce significant muscular damage. However, signs of myocellular stress and inflammation that were observed in the early phase of training and after the training intervention, respectively, may be facilitating the previously reported gains in myogenic satellite cell content and muscle hypertrophy. The present results improve our current knowledge about the physiological effects of low-load muscular contractions performed under blood flow restriction and may provide important information of relevance for future therapeutic treatment of muscular atrophy. ABSTRACT Previous studies indicate that low-load muscle contractions performed under local blood flow restriction (BFR) may initially induce muscle damage and stress. However, whether these factors are evoked with longitudinal BFR training remains unexplored at the myocellular level. Two distinct study protocols were conducted, covering 3 weeks (3 wk) or one week (1 wk). Subjects performed BFR exercise (100 mmHg, 20% 1RM) to concentric failure (BFRE) (3 wk/1 wk), while controls performed work-matched (LLE) (3 wk) or high-load (HLE; 70% 1RM) (1 wk) free-flow exercise. Muscle biopsies (3 wk) were obtained at baseline (Pre), 8 days into the intervention (Mid8), and 3 and 10 days after training cessation (Post3, Post10) to examine macrophage (M1/M2) content as well as heat shock protein (HSP27/70) and tenascin-C expression. Blood samples (1 wk) were collected before and after (0.1-24 h) the first and last training session to examine markers of muscle damage (creatine kinase), oxidative stress (total antibody capacity, glutathione) and inflammation (monocyte chemotactic protein-1, interleukin-6, tumour necrosis factor α). M1-macrophage content increased 108-165% with BFRE and LLE at Post3 (P < 0.05), while M2-macrophages increased (163%) with BFRE only (P < 0.01). Membrane and intracellular HSP27 expression increased 60-132% at Mid8 with BFRE (P < 0.05-0.01). No or only minor changes were observed in circulating markers of muscle damage, oxidative stress and inflammation. The amplitude, timing and localization of the above changes indicate that only limited muscle damage was evoked with BFRE. This study is the first to show that a period of high-frequency, low-load BFR training does not appear to induce general myocellular damage. However, signs of tissue inflammation and focal myocellular membrane stress and/or reorganization were observed that may be involved in the adaptation processes evoked by BFR muscle exercise.
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Effects of lifestyle intervention on soluble CD163, a macrophage activation marker, in patients with non-alcoholic fatty liver disease.
Rødgaard-Hansen, S, St George, A, Kazankov, K, Bauman, A, George, J, Grønbæk, H, Jon Møller, H
Scandinavian journal of clinical and laboratory investigation. 2017;(7):498-504
Abstract
OBJECTIVE Liver macrophages play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Soluble CD163 (sCD163), a macrophage-specific biomarker, reflects disease activity in the range of liver diseases. The impact of lifestyle intervention on sCD163 in adult NAFLD patients has not been investigated. MATERIAL AND METHODS We assessed 126 NAFLD patients participating in a lifestyle intervention study for sCD163 concentrations at baseline, after the three-month intervention period, and at long-term follow-up after 12 and 24 months. RESULTS The median sCD163 concentration at baseline was 2.59 mg/L (IQR = 1.78-3.63 mg/L). There was a significant decrease in sCD163 from baseline to three months follow-up (-0.64 mg/L, p < .001) with no difference between the four study groups (p = .6). At 12 and 24 months follow-up, the sCD163 concentrations had returned to baseline level (p = .3 and p = .1). Baseline sCD163 correlated with liver biomarkers and metabolic variables. There was a significantly greater decrease in sCD163 in patients who had a decrease in alanine aminotransferase (ALT) compared with patients with unchanged or increased ALT (-0.76 mg/L vs. -0.41 mg/L, p = .02), and in patients with a decrease in HOMA-IR compared with individuals with no decrease (-0.86 mg/L vs. -0.55 mg/L, p = .03). CONCLUSION sCD163 is associated with markers of liver necro-inflammation and glucose homoeostasis in NAFLD. Participation in a lifestyle intervention programme resulted in a significant reduction in sCD163. Our data support the utility of sCD163 as a biomarker for monitoring the efficacy of therapeutic interventions in NAFLD.
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Monoclonal antibody against macrophage colony-stimulating factor suppresses circulating monocytes and tissue macrophage function but does not alter cell infiltration/activation in cutaneous lesions or clinical outcomes in patients with cutaneous lupus erythematosus.
Masek-Hammerman, K, Peeva, E, Ahmad, A, Menon, S, Afsharvand, M, Peng Qu, R, Cheng, JB, Syed, J, Zhan, Y, O'Neil, SP, et al
Clinical and experimental immunology. 2016;(2):258-70
Abstract
This study's objective was to assess the effects of PD-0360324, a fully human immunoglobulin G2 monoclonal antibody against macrophage colony-stimulating factor in cutaneous lupus erythematosus (CLE). Patients with active subacute CLE or discoid lupus erythematosus were randomized to receive 100 or 150 mg PD-0360324 or placebo via intravenous infusion every 2 weeks for 3 months. Blood and urine samples were obtained pre- and post-treatment to analyse pharmacokinetics and pharmacodynamic changes in CD14(+) CD16(+) monocytes, urinary N-terminal telopeptide (uNTX), alanine/aspartate aminotransferases (ALT/AST) and creatine kinase (CK); tissue biopsy samples were taken to evaluate macrophage populations and T cells using immunohistochemistry. Clinical efficacy assessments included the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Among 28 randomized/analysed patients, peak/trough plasma concentrations increased in a greater-than-dose-proportional manner with dose increases from 100 to 150 mg. Statistically significant differences were observed between active treatment and placebo groups in changes from baseline in CD14(+) CD16(+) cells, uNTX, ALT, AST and CK levels at most time-points. The numbers, density and activation states of tissue macrophages and T cells did not change from baseline to treatment end. No between-group differences were seen in CLASI. Patients receiving PD-0360324 reported significantly more adverse events than those receiving placebo, but no serious adverse events. In patients with CLE, 100 and 150 mg PD-0360324 every 2 weeks for 3 months suppressed a subset of circulating monocytes and altered activity of some tissue macrophages without affecting cell populations in CLE skin lesions or improving clinical end-points.
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NP001 regulation of macrophage activation markers in ALS: a phase I clinical and biomarker study.
Miller, RG, Zhang, R, Block, G, Katz, J, Barohn, R, Kasarskis, E, Forshew, D, Gopalakrishnan, V, McGrath, MS
Amyotrophic lateral sclerosis & frontotemporal degeneration. 2014;(7-8):601-9
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Abstract
This is a phase I, placebo-controlled, single ascending dose safety and tolerability study of NP001 in patients with ALS. NP001 is a novel regulator of inflammatory macrophages and monocytes. As ALS progression is thought to be related to neuroinflammation, an additional objective of the study was to assess the effects of NP001 administration on monocyte activation markers. Thirty-two ALS patients were enrolled and received either placebo (eight) or one of four (six at each dose) ascending single i.v. doses (0.2, 0.8, 1.6 and 3.2 mg/kg NP001). Patients were monitored for safety, and blood monocyte immune activation markers CD16 and HLA-DR were assessed pre- and 24 h post-dosing. Changes from baseline were calculated. Results showed that NP001 was generally safe and well tolerated. Importantly, a single dose of NP001 caused a dose-dependent reduction in expression of monocyte CD16, a marker of monocyte activation/inflammation. Additionally, monocyte HLA-DR expression was also decreased in those patients with elevated values at baseline. In conclusion, these data indicate that NP001 has an acute effect on inflammatory monocytes in ALS patient blood. The potential for modulation of inflammation in the context of ALS disease progression will require further study with long-term follow-up.
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Effect of low-and high-dose atorvastatin on carotid artery distensibility using carotid magnetic resonance imaging -a post-hoc sub group analysis of ATHEROMA (Atorvastatin Therapy: Effects On Reduction Of Macrophage Activity) Study.
Sadat, U, Howarth, SP, Usman, A, Taviani, V, Tang, TY, Graves, MJ, Gillard, JH
Journal of atherosclerosis and thrombosis. 2013;(1):46-56
Abstract
AIM: To assess the effect of low-(10 mg) or high-(80 mg) dose atorvastatin on carotid artery distensibility in patients with asymptomatic carotid artery disease using carotid magnetic resonance imaging. METHODS Eighteen patients underwent initial 2-dimensional ECG gated-phase contrast carotid MR imaging and off-line applanation tonometry for distensibility assessment before randomisation to receive low- or high-dose statins and this was repeated at 12 weeks. Phase and magnitude images from the 2-D phase contrast acquisitions were used for quantification of distensibility and compliance coefficients and were compared between the low- and high-dose statin groups. RESULTS Both groups were comparable with regards to their demographics, co-morbidities and baseline cholesterol levels. After 12 weeks of high-dose statin administration, a significant decrease in LDL (p=0.003) and CRP (p=0.03) was observed. At 12 weeks, the distensibility coefficient of the common and internal carotid artery was found to be significantly higher (with respect to baseline) in the high-dose group (p=0.004 and p=0.007, respectively). The compliance coefficient was likewise found to be raised in the high-dose group when compared with the low-dose group [common carotid (p=0.002), internal carotid (p=0.009)]. CONCLUSIONS High-dose atorvastatin tends to reduce carotid arterial stiffness, as suggested by increased distensibility and compliance coefficients; however, these results need validation through large-scale trials to fully establish their possible use in clinical practice.
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Differential effects of endurance training and weight loss on plasma adiponectin multimers and adipose tissue macrophages in younger, moderately overweight men.
Auerbach, P, Nordby, P, Bendtsen, LQ, Mehlsen, JL, Basnet, SK, Vestergaard, H, Ploug, T, Stallknecht, B
American journal of physiology. Regulatory, integrative and comparative physiology. 2013;(5):R490-8
Abstract
Obese individuals are characterized by low circulating adiponectin concentrations and an increased number of macrophages in adipose tissue, which is believed to be causally associated with chronic low-grade inflammation and insulin resistance. Regular physical exercise decreases overall morbidity in obese subjects, which may be due to modulations of inflammatory pathways. In this randomized clinical trial we investigated the separate effects of endurance training-induced weight loss, diet-induced weight loss, and endurance training per se (without weight loss) on plasma adiponectin multimer composition (Western blotting) and adipose tissue macrophage content (immunohistochemistry) in young, moderately overweight men. Weight loss and endurance training per se decreased whole body fat percentage in an additive manner. No intervention-induced changes were observed for plasma total adiponectin. Surprisingly, endurance training, irrespectively of any associated weight loss, shifted the adiponectin multimer distribution toward a lower molecular weight (21% decrease in HMW/LMW, P = 0.015), whereas diet-induced weight loss shifted the distribution toward a higher molecular weight (42% increase in HMW/MMW, P < 0.001). Furthermore, endurance training per se increased the number of anti-inflammatory CD163⁺ macrophages [from 12.7 ± 2.1 (means ± SE) to 16.1 ± 3.1 CD163⁺ cells/100 adipocytes, P = 0.013], whereas diet-induced weight loss tended to decrease CD68⁺ macrophages in subcutaneous abdominal adipose tissue. Thus regular physical exercise influences systemic and adipose tissue inflammatory pathways differently than diet-induced weight loss in younger, moderately overweight men. Our data suggest that some of the health benefits of a physically active lifestyle may occur through modulations of anti- rather than pro-inflammatory pathways in young, overweight men.
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Atorvastatin reduces macrophage accumulation in atherosclerotic plaques: a comparison of a nonstatin-based regimen in patients undergoing carotid endarterectomy.
Puato, M, Faggin, E, Rattazzi, M, Zambon, A, Cipollone, F, Grego, F, Ganassin, L, Plebani, M, Mezzetti, A, Pauletto, P
Stroke. 2010;(6):1163-8
Abstract
BACKGROUND AND PURPOSE The object of our study was to compare the effect of high-dose vs low-dose atorvastatin vs nonstatin-based treatment (cholestyramine plus sitosterol) on cell composition of carotid plaque. METHODS We recruited 60 hypercholesterolemic patients (total cholesterol, 5.83-7.64 mmol/L) eligible for carotid endarterectomy. Three months before surgery, patients were randomized into 3 groups (n=20) receiving atorvastatin 10 mg/day (AT-10) or atorvastatin 80 mg/day (AT-80) or cholestyramine 8 g/day plus sitosterol 2.5 g/day. Analysis of cell composition was performed on endarterectomy specimens. RESULTS The 3 treatments resulted in a significant reduction of total cholesterol and low-density lipoprotein cholesterol (LDL-C), although the decrease in total cholesterol and LDL-C was of smaller magnitude in the cholestyramine plus sitosterol group. The 3 regimens did not influence the levels of inflammatory markers (including high-sensitivity C-reactive protein). Macrophage content was significantly lower in the AT-10 group plaques compared to the cholestyramine plus sitosterol group. It was further reduced in the AT-80 group plaques. These differences were no longer significant after adjustment for changes in LDL-C. No difference in lymphocyte number was observed among treatments, whereas the content of smooth muscle cells was higher in the AT- 80 group. An inverse association was observed between LDL-C changes in the 3 groups and macrophage content in the plaques. CONCLUSIONS Short-term treatment with high-dose statin is superior to a nonstatin lipid-lowering regimen in reducing the macrophage cell content within atherosclerotic lesions, but this effect was determined by the degree of LDL-C-lowering.
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The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) Study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease.
Tang, TY, Howarth, SP, Miller, SR, Graves, MJ, Patterson, AJ, U-King-Im, JM, Li, ZY, Walsh, SR, Brown, AP, Kirkpatrick, PJ, et al
Journal of the American College of Cardiology. 2009;(22):2039-50
Abstract
OBJECTIVES The aim of this study was to evaluate the effects of low-dose (10 mg) and high-dose (80 mg) atorvastatin on carotid plaque inflammation as determined by ultrasmall superparamagnetic iron oxide (USPIO)-enhanced carotid magnetic resonance imaging (MRI). The hypothesis was that treatment with 80 mg atorvastatin would demonstrate quantifiable changes in USPIO-enhanced MRI-defined inflammation within the first 3 months of therapy. BACKGROUND Preliminary studies indicate that USPIO-enhanced MRI can identify macrophage infiltration in human carotid atheroma in vivo and hence may be a surrogate marker of plaque inflammation. METHODS Forty-seven patients with carotid stenosis >40% on duplex ultrasonography and who demonstrated intraplaque accumulation of USPIO on MRI at baseline were randomly assigned in a balanced, double-blind manner to either 10 or 80 mg atorvastatin daily for 12 weeks. Baseline statin therapy was equivalent to 10 mg of atorvastatin or less. The primary end point was change from baseline in signal intensity (DeltaSI) on USPIO-enhanced MRI in carotid plaque at 6 and 12 weeks. RESULTS Twenty patients completed 12 weeks of treatment in each group. A significant reduction from baseline in USPIO-defined inflammation was observed in the 80-mg group at both 6 weeks (DeltaSI 0.13; p = 0.0003) and at 12 weeks (DeltaSI 0.20; p < 0.0001). No difference was observed with the low-dose regimen. The 80-mg atorvastatin dose significantly reduced total cholesterol by 15% (p = 0.0003) and low-density lipoprotein cholesterol by 29% (p = 0.0001) at 12 weeks. CONCLUSIONS Aggressive lipid-lowering therapy over a 3-month period is associated with significant reduction in USPIO-defined inflammation. USPIO-enhanced MRI methodology may be a useful imaging biomarker for the screening and assessment of therapeutic response to "anti-inflammatory" interventions in patients with atherosclerotic lesions. (Effects of Atorvastatin on Macrophage Activity and Plaque Inflammation Using Magnetic Resonance Imaging [ATHEROMA]; NCT00368589).
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A monounsaturated fatty acid-rich diet reduces macrophage uptake of plasma oxidised low-density lipoprotein in healthy young men.
Moreno, JA, López-Miranda, J, Pérez-Martínez, P, Marín, C, Moreno, R, Gómez, P, Paniagua, JA, Pérez-Jiménez, F
The British journal of nutrition. 2008;(3):569-75
Abstract
During atherogenesis, a pathological accumulation of lipids occurs within aortic intimal macrophages through uptake of plasma oxidised LDL (oxLDL). The aim of the present study was to determine whether macrophage uptake of plasma oxLDL and LDL susceptibility to oxidation may be determined by quantity and quality of dietary fat. Twenty healthy young men were subjected to three dietary periods, each lasting 4 weeks. The first was an SFA-enriched diet (38 % fat, 20 % SFA), which was followed by a carbohydrate (CHO)-rich diet (30 % fat, < 10 % SFA, 55 % CHO) or a MUFA olive oil-rich diet (38 % fat, 22 % MUFA) following a randomised cross-over design. After each diet period, LDL particles were oxidised with Cu ions to determine LDL susceptibility to oxidation and subsequently incubated with the U937-macrophage cell line to determine the percentage of uptake of plasma oxLDL. The shift from the MUFA diet to the SFA- or CHO-rich diets reduced the resistance of LDL particles to oxidation, decreasing lag time (P = 0.038) and increasing the propagation rate (P = 0.001). Furthermore, the MUFA-rich diet demonstrated reduced macrophage uptake of plasma oxLDL (P = 0.031) as compared with the SFA-rich diet. Finally, macrophage uptake of plasma oxLDL was correlated (r 0.45; P = 0.040) with total amount of conjugated dienes after LDL oxidation. Our data suggest that a MUFA-rich diet may have favourable effects on cardiovascular risk since it prevents the oxidative modifications of LDL and reduces macrophage uptake of plasma oxLDL.