Hypertonic saline attenuates the cytokine-induced pro-inflammatory signature in primary human lung epithelia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE94518 | GEO | 2017/02/06
SECONDARY ACCESSION(S): PRJNA371388
REPOSITORIES: GEO
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Project description:Rheumatoid arthritis (RA) is a debilitating autoimmune disease characterized by chronic inflammation and progressive destruction of joint tissue. It is also characterized by aberrant blood phenotypes including anemia and suppressed lymphopoiesis that contribute to morbidity in RA patients. However, the impact of RA on hematopoietic stem cells (HSC) has not been fully elucidated. Using a collagen-induced mouse model of human RA, we identified systemic inflammation and myeloid overproduction associated with activation of a myeloid differentiation gene program in HSC. Surprisingly, despite ongoing inflammation, HSC from arthritic mice remain in a quiescent state associated with activation of a proliferation arrest gene program. Strikingly, we found that inflammatory cytokine blockade using the interleukin-1 receptor antagonist anakinra led to an attenuation of inflammatory arthritis and myeloid expansion in the bone marrow of arthritic mice. In addition, anakinra reduced expression of inflammation-driven myeloid lineage and proliferation arrest gene programs in HSC of arthritic mice. Altogether, our findings show that inflammatory cytokine blockade can contribute to normalization of hematopoiesis in the context of chronic autoimmune arthritis.
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Project description:Skeletal muscle atrophy is associated with pro-inflammatory cytokines. Salidroside is a biologically active ingredient of Rhodiola rosea, which exhibits anti-inflammatory property. However, there is little known about the effect of salidroside on denervation-induced muscle atrophy. Therefore, the present study aimed to determine whether salidroside could protect against denervation-induced muscle atrophy and to clarify potential molecular mechanisms. Denervation caused progressive accumulation of inflammatory factors in skeletal muscle, especially interleukin 6 (IL6) and its receptor, and recombinant murine IL6 (rmIL6) local infusion could induce target muscle atrophy, suggesting that denervation induced inflammation in target muscles and the inflammation may trigger muscle wasting. Salidroside alleviated denervation-induced muscle atrophy and inhibited the production of IL6. Furthermore, the inhibition of phosphorylation of signal transducer and activator of transcription 3 (STAT3), and the decreased levels of suppressor of cytokine signaling (SOCS3), muscle RING finger protein-1 (MuRF1), atrophy F-box (atrogin-1), microtubule-associated protein light chain 3 beta (LC3B) and PTEN-induced putative kinase (PINK1) were observed in denervated muscles that were treated with salidroside. Finally, all of these responses to salidroside were replicated in neutralizing antibody against IL6. Taken together, these results suggest that salidroside alleviates denervation-induced inflammation response, thereby inhibits muscle proteolysis and muscle atrophy. Therefore, it was assumed that salidroside might be a potential therapeutic candidate to prevent muscle wasting.
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Project description:We examine the global effect of hBD3 on transcription in TLR4-stimulated macrophages and for the first time show that hBD3 inhibits the transcription of critical pro-inflammatory genes. Among the repressed genes we detect significant enrichment of groups involved in the positive regulation of NFkappaB including components of Toll-like receptor signaling pathways. Bone marrow derived macrophages from 3 separate mice were used for each treatment condition. ie macrophages from 3 mice were left untreated, macrophages from 3 mice were treated with LPS, macrophages from 3 mice were treated with LPS and hBD3, macrophages from 3 mice were treated with hBD3. We examined the differences in gene expression between each treatment group.
2012-01-01 | E-GEOD-25870 | biostudies-arrayexpress
Project description:IntroductionIn series of cases and animal models suffering hemorrhagic shock, the use of vasopressors has shown potential benefits regarding hemodynamics and tissue perfusion. Terlipressin is an analogue of vasopressin with a longer half-life that can be administered by bolus injection. We have previously observed that hypertonic albumin improves resuscitation following controlled hemorrhage in piglets. The aim of the present study was to analyze whether the treatment with the combination of terlipressin and hypertonic albumin can produce better hemodynamic and tissular perfusion parameters than normal saline or hypertonic albumin alone at early stages of hemorrhagic shock in an infant animal model.MethodsExperimental, randomized animal study including 39 2-to-3-month-old piglets. Thirty minutes after controlled 30 ml/kg bleed, pigs were randomized to receive either normal saline (NS) 30 ml/kg (n = 13), 5% albumin plus 3% hypertonic saline (AHS) 15 ml/kg (n = 13) or single bolus of terlipressin 15 μg/kg i.v. plus 5% albumin plus 3% hypertonic saline 15 ml/kg (TAHS) (n = 13) over 30 minutes. Global hemodynamic and tissular perfusion parameters were compared.ResultsAfter controlled bleed a significant decrease of blood pressure, cardiac index, central venous saturation, carotid and peripheral blood flow, brain saturation and an increase of heart rate, gastric PCO2 and lactate was observed. After treatment no significant differences in most hemodynamic (cardiac index, mean arterial pressure) and perfusion parameters (lactate, gastric PCO2, brain saturation, cutaneous blood flow) were observed between the three therapeutic groups. AHS and TAHS produced higher increase in stroke volume index and carotid blood flow than NS.ConclusionsIn this pediatric animal model of hypovolemic shock, albumin plus hypertonic saline with or without terlipressin achieved similar hemodynamics and perfusion parameters than twice the volume of NS. Addition of terlipressin did not produce better results than AHS.
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Project description: Not available
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Project description:Breast cancer survivors receiving chemotherapy often report increased anxiety and depression. However, the mechanism underlying chemotherapy-induced changes in affect remains unknown. We hypothesized that chemotherapy increases cytokine production, in turn altering exploratory and depressive-like behavior. To test this hypothesis, female Balb/C mice received two injections, separated by two weeks, of vehicle (0.9% saline) or a chemotherapeutic cocktail [9 mg/kg doxorubicin (A) and 90 mg/kg cyclophosphamide (C)]. Peripheral and central cytokine concentrations were increased one and seven days, respectively, after AC. Because of the beneficial effects of social enrichment on several diseases with inflammatory components, we examined whether social enrichment could attenuate the increase in peripheral and central cytokine production following chemotherapy administration. Socially isolated mice receiving AC therapy demonstrated increased depressive-like and exploratory behaviors with a concurrent increase in hippocampal IL-6. Whereas, group housing attenuated AC-induced IL-6 and depressive-like behavior. Next, we sought to determine whether central oxytocin may contribute to the protective effects of social housing after AC administration. Intracerebroventricular administration of oxytocin to socially isolated mice recapitulated the protective effects of social enrichment; specifically, oxytocin ameliorated the AC-induced effects on IL-6 and depressive-like behavior. Furthermore, administration of an oxytocin antagonist to group housed mice recapitulated the responses of socially isolated mice; specifically, AC increased depressive-like behavior and central IL-6. These data suggest a possible neuroprotective role for oxytocin following chemotherapy, via modulation of IL-6. This study adds to the growing literature detailing the negative behavioral effects of chemotherapy and provides further evidence that social enrichment may be beneficial to health.
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Project description:Uncontrolled inflammatory responses underlie the etiology of acute lung injury and acute distress respiratory syndrome, the most common late complications in trauma, the leading cause of death under the age of 59. Treatment with HTS decreases lung injury in clinical trials, rat models of trauma and hemorrhagic shock and inflammation in lung cell lines, although the mechanisms underlying these responses are still incompletely understood. Transcriptomics (RNaseq), proteomics, and U-13C-glucose tracing metabolomics experiments were performed to investigate the mechanisms of cellular responses to HTS treatment in primary small airway epithelial cells in the presence or absence of inflammatory injury mediated by a cocktail of cytokines (10 ng/mL of IFN?, IL-1?, and TNF?). Modestly hyperosmolar HTS has an anti-inflammatory effect, triggers the p53-p21 signaling axis, and deregulates mitochondrial metabolism while inducing minimal apoptosis in response to a second hit by cytokines. Decreased transcription of pro-inflammatory cytokines suggested a role for the tumor suppressor protein p53 in mediating the beneficial effects of the HTS treatment. The anti-inflammatory mechanisms induced by HTS involves p53 gene regulation, promotes cell cycle arrest, and prevents ROS formation and mitochondria depolarization. Pharmaceutical targeting of the p53-p21 axis may mimic or reinforce the beneficial effects mediated by HTS when sustained hypertonicity cannot be maintained.
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Project description:We examine the global effect of hBD3 on transcription in TLR4-stimulated macrophages and for the first time show that hBD3 inhibits the transcription of critical pro-inflammatory genes. Among the repressed genes we detect significant enrichment of groups involved in the positive regulation of NFkappaB including components of Toll-like receptor signaling pathways. Total RNA obtained from bone marrow derived macrophages (BMDM) that have been subjected to 6 hour treatment with KLA, KLA&hBD3, hBD3 or untreated. There are 3 biological replicates per group.
2012-01-01 | E-GEOD-25871 | biostudies-arrayexpress
Project description:To investigate the effects of hypertonic saline in the neurocritical care population.We retrospectively reviewed our hospital's use of hypertonic saline (HS) since March of 2005, and prospectively since October 2010. Comparisons were made between admission diagnoses, creatinine change (Cr), and HS formulation (3% NaCl, 3% NaCl/sodium acetate mix, and 23.4% NaCl) to patients receiving normal saline or lactated ringers. The patients (n = 1329) of the retrospective portion were identified. The data presented represents the first 230 patients with data.Significant differences in Acute Physiology and Chronic Health Evaluation II scores and Glasgow Coma Scale scores occurred between different saline formulations. No significant correlation of Cl(-) or Na(+) with Cr, nor with saline types, occurred. When dichotomized by diagnosis, significant correlations appear. Traumatic brain injury (TBI) patients demonstrated moderate correlation between Na(+) and Cr of 0.45. Stroke patients demonstrated weak correlations between Na(+) and Cr, and Cl(-) and Cr (0.19 for both). Patients receiving HS and not diagnosed with intracerebral hemorrhage, stroke, subarachnoid hemorrhage, or TBI demonstrated a weak but significant correlation between Cl(-) and Cr at 0.29.Cr directly correlates with Na(+) or Cl(-) in stroke, Na(+) in TBI, and Cl(-) in other populations. Prospective comparison of HS and renal function is needed.
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