Abstract Objective To test the hypothesis that the proinflammatory cytokine macrophage migration inhibitory factor (MIF) is elevated in the circulation of patients with chronic spinal cord injury ...(SCI) relative to uninjured subjects, and secondarily to identify additional immune mediators that are elevated in subjects with chronic SCI. Design Prospective, observational pilot study. Setting Outpatient clinic of a department of physical medicine and rehabilitation and research institute in an academic medical center. Participants Individuals with chronic (>1y from initial injury) SCI (n=22) and age- and sex-matched uninjured subjects (n=19). Interventions Not applicable. Main Outcome Measures Plasma levels of MIF, as determined by a commercially available multiplex suspension immunoassay. The relationship between MIF levels and clinical/demographic variables was also examined. As a secondary outcome, we evaluated other cytokines, chemokines, and growth factors. Results Plasma MIF levels were significantly higher in subjects with chronic SCI than in control subjects ( P <.001). Elevated MIF levels were not correlated significantly with any one clinical or demographic characteristic. Subjects with SCI also exhibited significantly higher plasma levels of monokine induced by interferon-gamma/chemokine C-X-C motif ligand 9 ( P <.03), macrophage colony stimulating factor ( P <.035), interleukin-3 ( P <.044), and stem cell growth factor beta (SCGF-β) ( P <.016). Among subjects with SCI, the levels of SCGF-β increased with the time from initial injury. Conclusions These data confirm the hypothesis that MIF is elevated in subjects with chronic SCI and identify additional novel immune mediators that are also elevated in these subjects. This study suggests the importance of examining the potential functional roles of MIF and other immune factors in subjects with chronic SCI.
This article summarizes advances in the field of host-microbe interactions in the gut. The human gut is home to a complex community of microbes (the microbiota) that plays a critical role in host ...nutrient acquisition and metabolism, development of intestinal epithelial cells, and host immune system. Genetic background, nutritional status, and environmental factors influence the structure and function of the gut microbiota. Networks for cell-cell communication include microbes actively communicating with microbes of the same and other species; host cells recognizing and interacting with commensal versus pathogenic organisms; and microbes releasing peptides that resemble peptide hormones of vertebrates, possibly influencing host cell function.
Objective Obesity and metabolic syndrome are associated with systemic inflammation and increased perinatal morbidity. Metformin improves metabolic and inflammatory biomarkers in nonpregnant adults. ...Using in vivo and in vitro models, we examined the effect of metformin on maternal and fetal inflammation. Study Design Female Wistar rats (6-7 weeks old) were fed a normal diet (NORM) or a high-fat/high-sugar diet (HCAL) for 5-6 weeks to induce obesity/metabolic syndrome. After mating with NORM-fed male rats, one-half of the HCAL-fed female rats received metformin (300 mg/kg, by mouth daily). All dams continued their respective diets until gestational day 19, at which time maternal and fetal outcomes were assessed. Maternal and fetal plasma and placentas were analyzed for metabolic and inflammatory markers. Cultured human placental JAR cells were pretreated with vehicle or metformin (10 μmol/L-2.5 mmol/L) before tumor necrosis factor α (TNF-α; 50 ng/mL), and supernatants were assayed for interleukin-6 (IL-6). Results HCAL rats gained more prepregnancy weight than NORM rats ( P = .03), had higher levels of plasma insulin and leptin, and exhibited dyslipidemia ( P < .05). Fetuses that were exposed to the HCAL diet had elevated plasma IL-6, TNF-α, and chemokine (C-C motif) ligand 2 levels ( P < .05) and enhanced placental TNF-α levels ( P < .05). Maternal metformin did not impact maternal markers but significantly decreased diet-induced TNF-α and chemokine (C-C motif) ligand 2 in the fetal plasma. Finally, metformin dose-dependently reduced TNF-α–induced IL-6 and IκBα levels in cultured placental JAR cells. Conclusion Diet induced-obesity/metabolic syndrome during pregnancy significantly enhanced fetal and placental cytokine production; maternal metformin reduced fetal cytokine levels. Similarly, metformin treatment of a placental cell line suppressed TNF-α–induced IL-6 levels by NFκB inhibitor.
Objective Intrauterine growth restriction (IUGR) is associated with increased inflammatory responses. We sought to investigate whether magnesium (Mg) attenuates inflammation and IUGR in a rat model. ...Study design Pregnant Wistar rats (12 weeks, gestational day 18) were randomly assigned to 1 of 4 groups: normal diet with bilateral uterine artery ligation (BL) (n = 6) or sham surgery (SH) (n = 5); and Mg chloride (MgCl2 ) 1% (wt/vol) in the drinking water throughout gestation + BL (MgBL) (n = 6) or SH (MgSH) (n = 5). Dams were euthanized 24 hours postsurgery (gestational day 19). Maternal plasma, fetal plasma (pooled), individual amniotic fluid (AF) samples, and placentas (PL) were collected and assessed from live fetal pups only (BL, n = 36; SH, n = 20; MgBL, n = 20; MgSH, n = 20). All samples were analyzed for cytokines/chemokines (interleukin IL-6, IL-1β, chemokine C-X-C motif ligand 1 CXCL1, chemokine C-C motif ligand 2 CCL2, and tumor necrosis factor TNF-α sensitivity <3 pg/mL) using a multiplex platform. Data were analyzed using Mann Whitney, analysis of variance, and Fisher exact tests. Results The incidence of IUGR (pup weight <10th percentile of SH) in the MgBL group was significantly lower (31%) than the BL group (86.3%) (relative risk, 0.36; 95% confidence interval, 0.2–0.6; P < .0001). BL significantly increased AF levels of IL-6, IL-1β, TNF-α ( P < .05), and CCL2 ( P < .001) vs SH and PL levels of IL-6, IL-1β, CCL2 and CXCL1 ( P < .001), and TNF-α ( P < .05) vs SH. Maternal MgCl2 supplementation significantly decreased IL-1β, TNF-α, and CCL2 levels in AF and IL-1β in PL tissues of MgBL vs BL rats ( P < .0001). Conclusion Maternal oral MgCl2 supplementation reduced BL-induced IUGR by 64% and suppressed cytokine/chemokine levels in the AF and PL.
Objective Magnesium sulfate is proposed to have neuroprotective effects in the offspring. We examined the effects of maternal magnesium sulfate administration on maternal and fetal inflammatory ...responses in a rat model of maternal infection. Study Design Pregnant rats were injected with saline, Gram-negative bacterial endotoxin lipopolysaccharide or lipopolysaccharide with magnesium sulfate (pre- and/or after lipopolysaccharide) to mimic infection. Maternal blood, amniotic fluid, fetal blood, and fetal brains were collected 4 hours after lipopolysaccharide and assayed for tumor necrosis factor, interleukin-6, monocyte chemoattractant protein-1, and growth-related oncogene-KC. In addition, the effect of magnesium sulfate on cytokine production by an astrocytoma cell line was assessed. Results Lipopolysaccharide administration induced tumor necrosis factor, interleukin-6, monocyte chemoattractant protein-1, and growth-related oncogene-KC expression in maternal and fetal compartments. Maternal magnesium sulfate treatment significantly attenuated lipopolysaccharide-induced multiple proinflammatory mediator levels in maternal and fetal compartments. Conclusion Antenatal magnesium sulfate administration significantly ameliorated maternal, fetal, and gestational tissue-associated inflammatory responses in an experimental model of maternal infection.
Objectives To investigate changes in urinary nerve growth factor (uNGF) in women with symptomatic detrusor overactivity (DO) following peripheral nerve evaluation (PNE) for sacral neuromodulation vs ...controls. Study Design There were 23 subjects with overactive bladder symptoms and DO who failed management with anticholinergics and 22 controls consented to participate in this prospective pilot study. Urine specimens were collected from controls at baseline for evaluation of uNGF and creatinine. Subjects were evaluated at baseline and 5 days after a trial of sacral nerve stimulation referred to as a PNE. Each visit included urine collection for uNGF and, Incontinence Quality of Life Questionnaire, Urinary Distress Inventory Questionnaire, postvoid residual volume, and a 3-day voiding diary. uNGF levels were measured by enzyme-linked immunosorbent assay and expressed as uNGF pg/creatinine mg. Results Subjects with DO had significantly higher baseline uNGF levels (corrected for creatinine) compared with controls (19.82 pg/mg vs 7.88 pg/mg, P < .002). Seventeen DO subjects underwent PNE and were evaluated at the end of the testing period. There was a significant improvement in quality of life scores for subjects after PNE compared with baseline (Urinary Distress Inventory Questionnaire: 7.0 vs 13.7, P < .001; Incontinence Quality of Life Questionnaire: 87.3 vs 52.8, P < .0001). Concordantly, uNGF levels significantly decreased from 17.23 pg/mg to 9.24 pg/mg ( P < .02) after PNE. Conclusion uNGF levels decrease with symptomatic response in DO subjects undergoing PNE. DO subjects had significantly higher uNGF at baseline vs controls, and uNGF levels significantly decreased after only 5 days of sacral nerve stimulation. These findings support a larger study to validate the use of uNGF as an objective tool to assess therapeutic outcome in patients undergoing PNE for sacral neuromodulation.
Objective Progesterone supplementation has been shown to be efficacious in preventing preterm birth. We sought to investigate the effects of progesterone on fetal inflammatory responses. Study Design ...Fetal mononuclear cells were isolated from umbilical cord blood and exposed to vehicle or progesterone (P4) for 1 hour prior to lipopolysaccharide (LPS) stimulation. Supernatants were assayed for tumor necrosis factor-α. Similar experiments were performed using cyclic adenosine monophosphate (cAMP) and progesterone modulators. The effect of P4 treatment on intracellular cAMP levels was also determined. Results LPS treatment led to a significant increase in cytokine production by fetal mononuclear cells. Despite the lack of detectable nuclear progesterone receptors, P4 suppressed this inflammatory response. R5020 (progesterone agonist), forskolin (cAMP inducer), and dibutyryl cAMP (cAMP agonist) all achieved immunosuppression. The cAMP antagonist, Rp-cAMP, blocked the inhibitory effect of progesterone. P4 significantly increased intracellular cAMP levels. Conclusion Progesterone rapidly suppresses the fetal inflammatory response, possibly via nongenomic activation of the cAMP cascade.
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