scholarly journals Intermittent reductions in respiratory neural activity elicit spinal TNF-α-independent, atypical PKC-dependent inactivity-induced phrenic motor facilitation

2015 ◽  
Vol 308 (8) ◽  
pp. R700-R707 ◽  
Author(s):  
Nathan A. Baertsch ◽  
Tracy L. Baker-Herman
Keyword(s):  
Neural Activity ◽  
Respiratory Control ◽  
Cellular Mechanisms ◽  
Compensatory Mechanisms ◽  
Atypical Pkc ◽  
System A ◽  
Tnf Α ◽  
Respiratory Plasticity ◽  
Dependent Form ◽  
Novel Therapeutic Strategies

In many neural networks, mechanisms of compensatory plasticity respond to prolonged reductions in neural activity by increasing cellular excitability or synaptic strength. In the respiratory control system, a prolonged reduction in synaptic inputs to the phrenic motor pool elicits a TNF-α- and atypical PKC-dependent form of spinal plasticity known as inactivity-induced phrenic motor facilitation (iPMF). Although iPMF may be elicited by a prolonged reduction in respiratory neural activity, iPMF is more efficiently induced when reduced respiratory neural activity (neural apnea) occurs intermittently. Mechanisms giving rise to iPMF following intermittent neural apnea are unknown. The purpose of this study was to test the hypothesis that iPMF following intermittent reductions in respiratory neural activity requires spinal TNF-α and aPKC. Phrenic motor output was recorded in anesthetized and ventilated rats exposed to brief intermittent (5, ∼1.25 min), brief sustained (∼6.25 min), or prolonged sustained (30 min) neural apnea. iPMF was elicited following brief intermittent and prolonged sustained neural apnea, but not following brief sustained neural apnea. Unlike iPMF following prolonged neural apnea, spinal TNF-α was not required to initiate iPMF during intermittent neural apnea; however, aPKC was still required for its stabilization. These results suggest that different patterns of respiratory neural activity induce iPMF through distinct cellular mechanisms but ultimately converge on a similar downstream pathway. Understanding the diverse cellular mechanisms that give rise to inactivity-induced respiratory plasticity may lead to development of novel therapeutic strategies to treat devastating respiratory control disorders when endogenous compensatory mechanisms fail.

Invited Review: Neuroplasticity in respiratory motor control

2003 ◽  
Vol 94 (1) ◽  
pp. 358-374 ◽  
Author(s):  
Gordon S. Mitchell ◽  
Stephen M. Johnson
Keyword(s):  
Control System ◽  
Neural Control ◽  
Developmental Plasticity ◽  
Biological Significance ◽  
Respiratory Control ◽  
System A ◽  
Cord Injury ◽  
Respiratory Plasticity ◽  
Considerable Work ◽  
Respiratory Gases

Although recent evidence demonstrates considerable neuroplasticity in the respiratory control system, a comprehensive conceptual framework is lacking. Our goals in this review are to define plasticity (and related neural properties) as it pertains to respiratory control and to discuss potential sites, mechanisms, and known categories of respiratory plasticity. Respiratory plasticity is defined as a persistent change in the neural control system based on prior experience. Plasticity may involve structural and/or functional alterations (most commonly both) and can arise from multiple cellular/synaptic mechanisms at different sites in the respiratory control system. Respiratory neuroplasticity is critically dependent on the establishment of necessary preconditions, the stimulus paradigm, the balance between opposing modulatory systems, age, gender, and genetics. Respiratory plasticity can be induced by hypoxia, hypercapnia, exercise, injury, stress, and pharmacological interventions or conditioning and occurs during development as well as in adults. Developmental plasticity is induced by experiences (e.g., altered respiratory gases) during sensitive developmental periods, thereby altering mature respiratory control. The same experience later in life has little or no effect. In adults, neuromodulation plays a prominent role in several forms of respiratory plasticity. For example, serotonergic modulation is thought to initiate and/or maintain respiratory plasticity following intermittent hypoxia, repeated hypercapnic exercise, spinal sensory denervation, spinal cord injury, and at least some conditioned reflexes. Considerable work is necessary before we fully appreciate the biological significance of respiratory plasticity, its underlying cellular/molecular and network mechanisms, and the potential to harness respiratory plasticity as a therapeutic tool.

scholarly journals Development of a Murine Model of Pyogenic Flexor Tenosynovitis

2020 ◽  
Author(s):  
Bowen Qiu ◽  
Justin Cobb ◽  
Alayna Loiselle ◽  
Constantinos Ketonis
Keyword(s):  
Murine Model ◽  
Tendon Sheath ◽  
Cellular Infiltrate ◽  
Cellular Mechanisms ◽  
Multiple Comparison Test ◽  
Hematoxylin Staining ◽  
Flexor Tendon Sheath ◽  
Pyogenic Flexor Tenosynovitis ◽  
Novel Therapeutic Strategies ◽  
Flexor Tenosynovitis

ABSTRACTBackgroundTo demonstrate the plausibility of a murine model of pyogenic flexor tenosynovitis.Methods2μL of sterile PBS or bioluminescent Xen29 Staphylococcus aureus was administered to the tendon sheath of 36 male C57BL/6J mice. The infectious course was monitored by bioluminescence (BLI) signal via IVIS imaging and recording of weight change. The infected hind paws were harvested at four time points: 24 hours, 72 hours, 1 week and 2 weeks for histopathology using Alcian Blue hematoxylin staining. Two-way ANOVA with Sidak’s multiple comparison test was used for statistical analysis.ResultsThe infected cohort displayed significantly elevated bioluminescent values, reductions in weight, and exhibited swelling of the infected digit throughout the course of infection. By day 7 most infected mice saw a substantial decrease in BLI signal intensity, however two infected mice exhibited persistent BLI intensity through day 14. Histopathology of the infected cohort showed tissue disorganization and the presence of a cellular infiltrate in and around the flexor tendon sheath.ConclusionsA murine model of pyogenic flexor tenosynovitis is possible. Further optimization of the model offers an experimental platform for investigation of the pathophysiology of pyogenic flexor tenosynovitis.Clinical RelevanceThis animal model can be utilized in order to elucidate the basic molecular/cellular mechanisms of pyogenic flexor tenosynovitis while simultaneously evaluating novel therapeutic strategies.

scholarly journals Senescence-associated changes in respiration and oxidative phosphorylation in primary human fibroblasts

2004 ◽  
Vol 380 (3) ◽  
pp. 919-928 ◽  
Author(s):  
Eveline HUTTER ◽  
Kathrin RENNER ◽  
Gerald PFISTER ◽  
Petra STÖCKL ◽  
Pidder JANSEN-DÜRR ◽  
...  
Keyword(s):  
Electron Transport ◽  
Oxidative Phosphorylation ◽  
Replicative Senescence ◽  
Citrate Synthase ◽  
Human Fibroblasts ◽  
Respiratory Control ◽  
Compensatory Mechanisms ◽  
Intact Cells ◽  
Atp Production ◽  
Human Diploid Fibroblasts

Limitation of lifespan in replicative senescence is related to oxidative stress, which is probably both the cause and consequence of impaired mitochondrial respiratory function. The respiration of senescent human diploid fibroblasts was analysed by highresolution respirometry. To rule out cell-cycle effects, proliferating and growth-arrested young fibroblasts were used as controls. Uncoupled respiration, as normalized to citrate synthase activity, remained unchanged, reflecting a constant capacity of the respiratory chain. Oligomycin-inhibited respiration, however, was significantly increased in mitochondria of senescent cells, indicating a lower coupling of electron transport with phosphorylation. In contrast, growth-arrested young fibroblasts exhibited a higher coupling state compared with proliferating controls. In intact cells, partial uncoupling may lead to either decreased oxidative ATP production or a compensatory increase in routine respiration. To distinguish between these alternatives, we subtracted oligomycin-inhibited respiration from routine respiration, which allowed us to determine the part of respiratory activity coupled with ATP production. Despite substantial differences in the respiratory control ratio, ranging from 4 to 11 in the different experimental groups, a fixed proportion of respiratory capacity was maintained for coupled oxidative phosphorylation in all the experimental groups. This finding indicates that the senescent cells fully compensate for increased proton leakage by enhanced electron-transport activity in the routine state. These results provide a new insight into age-associated defects in mitochondrial function and compensatory mechanisms in intact cells.

Adaptation in the respiratory control system

2003 ◽  
Vol 81 (8) ◽  
pp. 765-773 ◽  
Author(s):  
James Duffin ◽  
Safraaz Mahamed
Keyword(s):  
Experimental Data ◽  
Control System ◽  
Steady State ◽  
Graphical Model ◽  
Respiratory Control ◽  
Ventilatory Responses ◽  
System A ◽  
Hypoxia Adaptation ◽  
Peripheral Chemoreflex

Exposure to hypoxia, whether for short or prolonged periods or for repeated episodes, produces alterations in the ventilatory responses. This review presents evidence that these adaptations are likely to be mediated by adaptations in the respiratory chemoreflexes, particularly the peripheral chemoreflex, and proposes models of respiratory control explaining the observed changes in ventilation. After a brief introduction to the respiratory control system, a graphical model is developed that illustrates the operation of the system in the steady state, which will be used later. Next, the adaptations in ventilatory responses to hypoxia that have been observed are described, and methods of measuring the alterations in the chemoreflexes that might account for them are discussed. Finally, experimental data supporting the view that changes in the activity of the peripheral chemoreflex can account for the ventilatory adaptations to hypoxia are presented and incorporated into models of chemoreflex behaviour during exposures to hypoxia of various durations.Key words: respiration, chemoreflexes, hypoxia, adaptation, models.

scholarly journals Epigenetic Mechanisms of Cardioprotection: Focus is on Activation of Sirtuins

2021 ◽  
Vol 11 (6) ◽  
pp. 424-432
Author(s):  
K. A. Aitbaev ◽  
I. T. Murkamilov ◽  
Zh. A. Murkamilova ◽  
I. O. Kudaibergenova ◽  
F. A. Yusupov
Keyword(s):  
Oxidative Stress ◽  
Vascular System ◽  
Epigenetic Mechanisms ◽  
Molecular Signaling ◽  
Cellular Mechanisms ◽  
Pharmacological Agents ◽  
System A ◽  
Age Related ◽  
Aging Properties ◽  
Common Sign

Oxidative stress is a common sign of aging and cardiovascular disease (CVD), including atherosclerosis, heart failure, hypertension, diabetes mellitus and other diseases of the vascular system. In this regard, in recent years, researchers have shown increased interest in sirtuins (SIRTs) — stress adapters and epigenetic enzymes involved in cellular mechanisms for controlling age-related pathologies, cancer and CVD. Among sirtuins, of which there are seven in mammals (SIRT1-SIRT7), SIRT1 and SIRT6 possess the most cardioprotective, anti-inflammatory, atheroprotective and anti-aging properties. In this review, we present a comprehensive analysis of the latest developments in the field of cellular and molecular signaling pathways controlled by two post-translational modifiers — SIRT1 and SIRT6, which have proven their worth as tools to reduce inflammation and oxidative stress at the level of the cardiovascular system. A deeper understanding of the epigenetic mechanisms through which SIRT1 and SIRT6 exert their cardioprotective effect will have widespread implications and will accelerate the development of selective and effective pharmacological agents for modulating sirtuins for the prevention and treatment of CVD.

scholarly journals HIV-1 Nef Protein Affects Cytokine and Extracellular Vesicles Production in the GEN2.2 Plasmacytoid Dendritic Cell Line

Viruses ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 74
Author(s):  
Alessandra Aiello ◽  
Flavia Giannessi ◽  
Zulema Antonia Percario ◽  
Katia Fecchi ◽  
Claudia Arenaccio ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Cell Line ◽  
Plasmacytoid Dendritic Cell ◽  
Cell Subset ◽  
Extracellular Vesicle ◽  
Type I ◽  
Dendritic Cell Subset ◽  
System A ◽  
New Information ◽  
Tnf Α

Plasmacytoid dendritic cells (pDCs) are a unique dendritic cell subset specialized in type I interferon production, whose role in Human Immunodeficiency Virus (HIV) infection and pathogenesis is complex and not yet well defined. Considering the crucial role of the accessory protein Nef in HIV pathogenicity, possible alterations in intracellular signalling and extracellular vesicle (EV) release induced by exogenous Nef on uninfected pDCs have been investigated. As an experimental model system, a human plasmacytoid dendritic cell line, GEN2.2, stimulated with a myristoylated recombinant NefSF2 protein was employed. In GEN2.2 cells, Nef treatment induced the tyrosine phosphorylation of STAT-1 and STAT-2 and the production of a set of cytokines, chemokines and growth factors including IP-10, MIP-1β, MCP-1, IL-8, TNF-α and G-CSF. The released factors differed both in type and amount from those released by macrophages treated with the same viral protein. Moreover, Nef treatment slightly reduces the production of small EVs, and the protein was found associated with the small (size < 200 nm) but not the medium/large vesicles (size > 200 nm) collected from GEN2.2 cells. These results add new information on the interactions between this virulence factor and uninfected pDCs, and may provide the basis for further studies on the interactions of Nef protein with primary pDCs.

scholarly journals Simvastatin Inhibits CYR61 Expression in Orbital Fibroblasts in Graves’ Ophthalmopathy through the Regulation of FoxO3a Signaling

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Yi-Hsuan Wei ◽  
Shu-Lang Liao ◽  
Chia-Chun Wang ◽  
Sen-Hsu Wang ◽  
Wan-Chun Tang ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Protective Effects ◽  
Cellular Mechanisms ◽  
Graves Ophthalmopathy ◽  
Potential Biomarker ◽  
Tnf Α ◽  
Orbital Tissue ◽  
Proinflammatory Role ◽  
And Migration ◽  
Orbital Fibroblasts

Graves’ ophthalmopathy (GO), which is characterized by orbital tissue inflammation, expansion, and fibrosis, is the ocular manifestation in 25% to 50% of patients with Graves’ disease. As the pathology of GO is driven by autoimmune inflammation, many proinflammatory cytokines/chemokines, including TNF-α, IL-1β, IL-6, and CCL20, are crucial in the pathogenesis of GO to activate the orbital fibroblasts. Cysteine-rich protein 61 (CYR61), which is known to regulate cell proliferation, adhesion, and migration, plays a proinflammatory role in the pathogenesis of many inflammatory diseases, such as rheumatoid arthritis. CYR61 was considered a potential biomarker of GO in recent studies. Statins, which are cholesterol-lowering drugs, were found to reduce the risk of GO, probably through their anti-inflammatory and immunomodulatory effects. In this study, we established a link between CYR61 and statins in the pathogenesis and potential treatment for GO. Firstly, our data showed the overexpression of CYR61 in the orbital tissue ( n = 4 ) and serum specimens ( n = 6 ) obtained from the patients with inactive GO. CYR61 could induce the production of IL-6 and CCL20 in cultured GO orbital fibroblasts. The expression of CYR61 in cultured GO orbital fibroblasts was upregulated via TNF-α stimulation. Secondly, we pretreated cultured GO orbital fibroblasts using simvastatin, a statin, followed by TNF-α stimulation. The data revealed that simvastatin could inhibit TNF-α-induced CYR61 expression by modulating the activity of transcription factor FoxO3a. Our results provided insights into some cellular mechanisms that may explain the possible protective effects of simvastatin against the development of GO.

Effect of Inflammation on the Osmotic Response of Nucleus Pulposus Cells

2012 ◽  
Author(s):  
Robert Maidhof ◽  
Neena Rajan ◽  
Nadeen O. Chahine
Keyword(s):  
Nucleus Pulposus ◽  
Biomechanical Properties ◽  
Nucleus Pulposus Cells ◽  
Cellular Mechanisms ◽  
Osmotic Response ◽  
Tnf Α ◽  
Disc Cells ◽  
Cytokine Stimulation ◽  
Ivd Degeneration

Intervertebral disc (IVD) degeneration is accompanied by elevated levels of pro-inflammatory cytokines, particularly IL-1β and TNF-α [1]. Disc cells from the nucleus pulposus (NPs) respond to cytokine stimulation with increased catabolic breakdown of the tissue, resulting in a positive feedback of disc integrity loss and further inflammation [2]. Previous studies by our group have examined the response of NP cells to Toll-Like Receptor-4 (TLR-4) activation through stimulation with lipopolysaccharide (LPS). TLR-4 is a pattern recognition receptor that is activated in innate immunity and by polysaccharide fragments from degenerated proteoglycans. TLR-4 activation by LPS results in stimulation of multiple cytokines by NP cells [3]. Moreover, we have shown that in vivo LPS injection results in catabolic changes in the IVD, including matrix breakdown, decrease in biomechanical properties and loss of disc height [4]. However, the specific cellular mechanisms for these catabolic changes remain to be elucidated.

scholarly journals Emerging Molecular Targets for the Treatment of Refractory Sarcoidosis

2020 ◽  
Vol 7 ◽  
Author(s):  
Gonçalo Boleto ◽  
Matheus Vieira ◽  
Anne Claire Desbois ◽  
David Saadoun ◽  
Patrice Cacoub
Keyword(s):  
Case Series ◽  
Unknown Origin ◽  
Janus Kinase ◽  
Interferon Response ◽  
T Helper 1 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Case Series Report ◽  
Factor Alpha ◽  
Novel Therapeutic Strategies

Sarcoidosis is a multisystem granulomatous disease of unknown origin that has variable clinical course and can affect nearly any organ. It has a chronic course in about 25% of patients. Corticosteroids (CS) are the cornerstone of therapy but their long-term use is associated with cumulative toxicity. Commonly used CS-sparing agents include methotrexate, cyclophosphamide, azathioprine, and mycophenolate mofetil. Twenty to forty percentage of sarcoidosis patients are refractory to these therapies or develop severe adverse events. Therefore, additional and targeted CS-sparing agents are needed for chronic sarcoidosis. Macrophage activation, interferon response, and formation of the granuloma are mainly mediated by T helper-1 responses. Different pro-inflammatory cytokines such as interleukin (IL)-8, IL-12, IL-6, and tumor necrosis factor-alpha (TNF-α) have been shown to be highly expressed in sarcoidosis-affected tissues. As a result of increased production of these cytokines, Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is constitutively active in sarcoidosis. Several studies of biological agents that target TNF-α have reported their efficacy and appear today as a second line option in refractory sarcoidosis. Some case series report a positive effect of tocilizumab an anti-IL-6 monoclonal antibody in this setting. More recently, JAK inhibition appears as a new promising strategy. This review highlights key advances on the management of chronic refractory sarcoidosis. Novel therapeutic strategies and treatment agents to manage the disease are described.

Sign in / Sign up

Export Citation Format

Share Document