Stikkordarkiv: Betennelser

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The vagus nerve and the inflammatory reflex: wandering on a new treatment paradigm for systemic inflammation and sepsis.

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Mer om vagusnerven og betennelsesdemping

http://www.ncbi.nlm.nih.gov/pubmed/22913335

Abstract
BACKGROUND:
The immune system protects the host against dangerous pathogens and toxins. The central nervous system is charged with monitoring and coordinating appropriate responses to internal and external stimuli. The inflammatory reflex sits at the crossroads of these crucial homeostatic systems. This review highlights how the vagus nerve-mediated inflammatory reflex facilitates rapid and specific exchange of information between the nervous and immune systems to prevent tissue injury and infection.
METHODS:
Review of the pertinent English-language literature. Nearly two decades of research has elucidated some of the essential anatomic, physiologic, and molecular connections of the inflammatory reflex. The original descriptions of how these key components contribute to afferent and efferent anti-inflammatory vagus nerve signaling are summarized.
RESULTS:
The central nervous system recognizes peripheral inflammation via afferent vagus nerve signaling. The brain can attenuate peripheral innate immune responses, including pro-inflammatory cytokine production, leukocyte recruitment, and nuclear factor kappa β activation via α7-nicotinic acetylcholine receptor subunit-dependent, T-lymphocyte-dependent, vagus nerve signaling to spleen. This efferent arm of the inflammatory reflex is referred to as the «cholinergic anti-inflammatory pathway.» Activation of this pathway via vagus nerve stimulation or pharmacologic α7 agonists prevents tissue injury in multiple models of systemic inflammation, shock, and sepsis.
CONCLUSIONS:
The vagus nerve-mediated inflammatory reflex is a powerful ally in the fight against lethal tissue damage after injury and infection. Further studies will help translate the beneficial effects of this pathway into clinical use for our surgical patients.

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Rapid changes in histone deacetylases and inflammatory gene expression in expert meditators.

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Om hvordan 1 hel dag med meditasjon endrer genene som styrer betennelser.

http://www.ncbi.nlm.nih.gov/pubmed/24485481/

Abstract

BACKGROUND:

A growing body of research shows that mindfulness meditation can alter neural, behavioral and biochemical processes. However, the mechanisms responsible for such clinically relevant effects remain elusive.

METHODS:

Here we explored the impact of a day of intensive practice of mindfulness meditation in experienced subjects (n=19) on the expression of circadian, chromatin modulatory and inflammatory genes in peripheral blood mononuclear cells (PBMC). In parallel, we analyzed a control group of subjects with no meditation experience who engaged in leisure activities in the same environment (n=21). PBMC from all participants were obtained before (t1) and after (t2) the intervention (t2-t1=8h) and gene expression was analyzed using custom pathway focused quantitative-real time PCR assays. Both groups were also presented with the Trier Social Stress Test (TSST).

RESULTS:

Core clock gene expression at baseline (t1) was similar between groups and their rhythmicity was not influenced in meditators by the intensive day of practice. Similarly, we found that all the epigenetic regulatory enzymes and inflammatory genes analyzed exhibited similar basal expression levels in the two groups. In contrast, after the brief intervention we detected reduced expression of histone deacetylase genes (HDAC 2, 3 and 9), alterations in global modification of histones (H4ac; H3K4me3) and decreased expression of pro-inflammatory genes (RIPK2 and COX2) in meditators compared with controls. We found that the expression of RIPK2 and HDAC2 genes was associated with a faster cortisol recovery to the TSST in both groups.

CONCLUSIONS:

The regulation of HDACs and inflammatory pathways may represent some of the mechanisms underlying the therapeutic potential of mindfulness-based interventions. Our findings set the foundation for future studies to further assess meditation strategies for the treatment of chronic inflammatory conditions.

 

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Cytokine Dysregulation, Inflammation and Well-Being

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Om hvordan cytokiner kobler nervesystem og immunsystem med betennelser. Den forteller at betennelser er utgangspunktet for de fleste livsstilsykdommer og smertetilstander som følge av autoimmunesykdommer.

http://www.karger.com/Article/Abstract/87104

Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis, health, and well-being. Like the stress response, the inflammatory reaction is crucial for survival and is meant to be tailored to the stimulus and time. A full-fledged systemic inflammatory reaction results in stimulation of four major programs: the acute-phase reaction, the sickness syndrome, the pain program, and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Common human diseases such as atopy/allergy, autoimmunity, chronic infections and sepsis are characterized by a dysregulation of the pro- versus anti-inflammatory and T helper (Th)1versus Th2 cytokine balance. Recent evidence also indicates the involvement of pro-inflammatory cytokines in the pathogenesis of atherosclerosis and major depression, and conditions such as visceral-type obesity, metabolic syndrome and sleep disturbances. During inflammation, the activation of the stress system, through induction of a Th2 shift, protects the organism from systemic ‘overshooting’ with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones may actually facilitate inflammation through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis factor-α and C-reactive protein production and through activation of the corticotropin-releasing hormone/substance P-histamine axis. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the ‘systemic anti-inflammatory feedback’ and/or ‘hyperactivity’ of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression, and atherosclerosis. These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health. These hypotheses require further investigation, but the answers should provide critical insights into mechanisms underlying a variety of common human immune-related diseases.

 

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Free oxygen radicals in whole blood correlate strongly with high-sensitivity C-reactive protein.

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Nevner at mengden ROS (Reactive Oxygen Species) i blod korresponderer direkte til CRP, en betenneslsesmarkør.

http://www.ncbi.nlm.nih.gov/pubmed/21291700

BACKGROUND:

Increased concentrations of reactive oxygen molecules are believed to be a driving force in inflammation. Although evident in tissue culture and animal models, it has been difficult to link reactive oxygen species (ROS) and inflammatory markers in humans. In patients recruited to represent a broad spectrum of risk factors, we investigated the relationship between the plasma concentration of oxygen radicals and high-sensitivity C-reactive protein (hs-CRP), utilizing a new chemistry with an easily oxidized chromophore.

METHODS:

ROS and hs-CRP were measured in blood from 59 fasting subjects selected to have variable risk predicted by classical risk factors. ROS were determined using the free oxygen radical monitor, which is an indirect colorimetric assay for the concentration of hydroperoxides in whole blood.

RESULTS:

Using log transformation, the correlation between ROS and hs-CRP was r = 0.505 (P < 0.0001). This relationship between ROS and hs-CRP was comparable (r = 0.527, P = 0.001) in the subgroup not currently on statin therapy (n = 39). ROS were not correlated with Framingham risk, r = -0.027 (P = 0.84).

CONCLUSION:

ROS directly measured in human blood correlates strongly with hs-CRP.

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Heart rate variability is independently associated with C-reactive protein but not with Serum amyloid A. The Cardiovascular Risk in Young Finns Study.

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Nevner hvordan lav HRV gir økt betennelsesnivå ved høyer alder.

http://www.ncbi.nlm.nih.gov/pubmed/21323913

Abstract

BACKGROUND:

Increased levels of C-reactive protein (CRP) and serum amyloid A (SAA) are associated with an increased risk of cardiovascular disease. It is hypothesized that dysregulation of the autonomic nervous system (ANS) leads to increased inflammation via the cholinergic anti-inflammatory pathway. Heart rate variability (HRV) is a marker of ANS function. HRV has been shown to be associated with CRP levels. Currently, there are no studies addressing the relationship between HRV and SAA.

DESIGN:

The purpose of this study was to compare the associations between HRV, CRP and SAA in healthy young adults. CRP and SAA concentrations and short-term HRV indices [high frequency (HF), low frequency (LF), total spectral component of HRV, root mean square differences of successive R-R intervals, the standard deviation of all R-R intervals and ratio between LF and HF) were measured in 1601 men and women aged 24-39 taking part in the Cardiovascular Risk in Young Finns study.

RESULTS:

A significant inverse correlation (P < 0·05) between HRV indices and inflammatory markers was observed. However, in linear regression analyses, only inverse association between HRV indices and CRP levels remained significant (P < 0·05), while association between HRV indices and SAA levels was attenuated to the null (P > 0·05) after adjusting for age, sex, body mass index, cholesterol levels, leptin and other common traditional cardiovascular risk factors.

CONCLUSIONS:

Reduced HRV indices are independently associated with increased CRP levels, but not with SAA levels. This association supports the hypothesis that dysregulation of the ANS may lead to increased inflammation early in adulthood.

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C-reactive protein, heart rate variability and prognosis in community subjects with no apparent heart disease.

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Nevner hvordan HRV er relatert til CRP (betennelser) og overlevelse i kliniske situasjoner.

http://www.ncbi.nlm.nih.gov/pubmed/16961675

Abstract

OBJECTIVES:

Increased C-reactive protein (CRP) and reduced heart rate variability (HRV) both indicate poor prognosis. An inverse association between HRV and CRP has been reported, suggesting an interaction between inflammatory and autonomic systems. However, the prognostic impact of this interaction has not been studied. We thus investigated the prognostic impact of CRP, HRV and their combinations.

DESIGN:

Population-based study.

SUBJECTS:

A total of 638 middle-aged and elderly subjects with no apparent heart disease from community.

METHODS:

All were studied by clinical and laboratory examinations, and 24-h Holter monitoring. Four time domain measures of HRV were studied. All were prospectively followed for up to 5 years.

RESULTS:

Mean age was 64 years (55-75). During the follow-up, 46 total deaths and 11 cases of definite acute myocardial infarction were observed. Both CRP and three of four HRV measures were significantly associated with increased rate of death or myocardial infarction. In a Cox model with CRP >or=2.5 microg mL(-1), standard deviation for the mean value of the time between normal complexes <or=100 ms, and their combination, hazard ratio and 95% CI for subjects with both abnormalities was 3.20 (1.55-6.56), P = 0.0016, and for subjects with either abnormality 1.63(0.83-3.20), P = 0.15, after adjustment for conventional risk factors. The combination of CRP and other measures of HRV gave similar results. This indicates an interaction between CRP and HRV with a synergistic effect.

CONCLUSIONS:

The combination of CRP and HRV or heart rate (HR) predicts death and myocardial infarction with synergism, indicating interaction between inflammatory and autonomic systems with a prognostic significance.

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Decreased heart rate variability is associated with higher levels of inflammation in middle-aged men.

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Nevner hvordan HRV relateres til CRP (betennelser) og risiko for hjerte/kar problemer.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587932/

Abstract

BACKGROUND:

Many traditional risk factors for coronary artery disease (CAD) are associated with altered autonomic function. Inflammation may provide a link between risk factors, autonomic dysfunction, and CAD. We examined the association between heart rate variability (HRV), a measure of autonomic function, and inflammation, measured by C-reactive protein (CRP) and interleukin-6 (IL-6).

METHODS:

We examined 264 middle-aged male twins free of symptomatic CAD. All underwent ambulatory electrocardiogram monitoring and 24-hour ultra low, very low, low, and high-frequency power were calculated using power spectral analysis. C-reactive protein and IL-6 were measured, and risk factors including age, smoking, hypertension, lipids, diabetes, body mass index (BMI), depression, and physical activity were assessed.

RESULTS:

Physical activity, BMI, high-density lipoprotein cholesterol, smoking, depression, and hypertension were directly associated with CRP and IL-6 and inversely associated with one or more HRV variables. There was a graded inverse relationship between all HRV parameters (except high frequency) and CRP and IL-6. After adjustment for age, BMI, activity, high-density lipoprotein, smoking, hypertension, depression, and diabetes, ultra low frequency and very low frequency remained significant predictors of CRP (P < .01).

CONCLUSIONS:

C-reactive protein is associated with decreased HRV, even after controlling for traditional CAD risk factors. Autonomic dysregulation leading to inflammation may represent one pathway through which traditional risk factors promote development of CAD.

Heart rate variability (HRV), a measure of beat-to-beat heart rate fluctuations over time, is an established measure of autonomic function.17 A relationship between HRV and inflammation, as measured by serum markers such as interleukin 6 (IL-6) and C reactive protein (CRP), has been demonstrated in patients with congestive heart failure and acute coronary syndromes.18–20 Studies of populations free of overt cardiac disease have suggested similar relationships.21–23

Both CRP and IL-6 were correlated with all HRV variables except HF, most strongly with ULF and VLF. When the group was categorized into tertiles based on HRV variables (Figure 1), CRP increased as HRV decreased. Plasma concentrations of CRP of those in the lowest tertile of ULF and VLF were more than twice that of those in the highest tertile. A similar pattern was seen for IL-6.

 

In middle-aged men free of cardiovascular disease, autonomic dysfunction, as demonstrated by decreased HRV, was associated with higher levels of the inflammatory biomarkers CRP and IL-6. Decreased long-term HRV (ULF and VLF) remained an independent predictor of plasma concentration of CRP after adjustment for CAD risk factors associated with both autonomic dysfunction and inflammation.

The inflammatory process is complex, and only two markers were examined in this study. While the association between HRV and CRP remained significant after controlling for other factors, that between HRV and IL-6 did not. IL-6 has a short half-life,31 and varies throughout the day, showing circadian variation,31 whereas CRP levels remain stable over 24 hours.32 This may explain why HRV, measured over 24-hours, showed a stronger association with CRP than IL-6.

Sympathetic stimulation inhibits vagal output38, and it is also possible that the relationships seen here between HRV and inflammation were a reflection of sympathetic effects (ie, that low HRV was a marker for increased sympathetic activity) or that the two may have independent effects.

 

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Vagal tone and the inflammatory reflex

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En studie som beskriver mekanismene bak hvordan vagus nerven henger sammen med immunsystemet. Med en sterk vagusnerve (høy HRV) kan betennelser dempes.

http://www.ccjm.org/content/76/Suppl_2/S23.long

Inhibition of sympathoexcitatory circuits is influenced by cerebral structures and mediated via vagal mechanisms. Studies of pharmacologic blockade of the prefrontal cortex together with neuroimaging studies support the role of the right hemisphere in parasympathetic control of the heart via its connection with the right vagus nerve. Neural mechanisms also regulate inflammation; vagus nerve activity inhibits macrophage activation and the synthesis of tumor necrosis factor in the reticuloendothelial system through the release of acetylcholine. Data suggest an association between heart rate variability and inflammation that may support the concept of a cholinergic anti-inflammatory pathway.

The neurovisceral integration model of cardiac vagal tone integrates autonomic, attentional, and affective systems into a functional and structural network. This neural network can be indexed by heart rate variability (HRV). High HRV is associated with greater prefrontal inhibitory tone. A lack of inhibition leads to undifferentiated threat responses to environmental challenges.

The cholinergic anti-inflammatory pathway

Acetylcholine and parasympathetic tone inhibit proinflammatory cytokines such as interleukin (IL)-6. These proinflammatory cytokines are under tonic inhibitory control via the vagus nerve, and this function may have important implications for health and disease.5

The cholinergic anti-inflammatory pathway is associated with efferent activity in the vagus nerve, leading to acetylcholine release in the reticuloendothelial system that includes the liver, heart, spleen, and gastrointestinal tract. Acetylcholine interacts with the alpha-7 nicotinic receptor on tissue macrophages to inhibit the release of proinflammatory cytokines, but not anti-inflammatory cytokines such as IL-10.

Approximately 80% of the fibers of the vagus nerve are sensory; ie, they sense the presence of proinflammatory cytokines and convey the signal to the brain. Efferent vagus nerve activity leads to the release of acetylcholine, which inhibits tumor necrosis factor (TNF)-alpha on the macrophages. Cytokine regulation also involves the sympathetic nervous system and the endocrine system (the hypothalamic-pituitary axis).

Inverse relationship between HRV and CRP

In a study of 613 airplane factory workers in southern Germany, vagally mediated HRV was inversely related to high-sensitivity CRP in men and premenopausal women, even after controlling for urinary norepinephrine as an index of sympathetic activity.6

Inverse relationship between HRV and fibrinogen

In a related report from the same study, vagal modulation of fibrinogen was investigated.7 Fibrinogen is a large glycoprotein that is synthesized by the liver. Plasma fibrinogen is a measure of systemic inflammation crucially involved in atherosclerosis.

CONCLUSION

The brain and the heart are intimately connected. Both epidemiologic and experimental data suggest an association between HRV and inflammation, including similar neural mechanisms. Evidence of an association between HRV and inflammation supports the concept of a cholinergic anti-inflammatory pathway.

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The inflammatory reflex: the role of the vagus nerve in regulation of immune functions

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Nevner mekanismene bak hvordan vagus nerven demper betennelsesreaksjoner og kan bidra i autoimmune sykdommer.

http://www.ncbi.nlm.nih.gov/pubmed/22263327

Abstract

Experimental studies published in past years have shown an important role of the vagus nerve in regulating immune functions. Afferent pathways of this cranial nerve transmit signals related to tissue damage and immune reactions to the brain stem. After central processing of these signals, activated efferent vagal pathways modulate inflammatory reactions through inhibiting the synthesis and secretion of pro-inflammatory cytokines by immune cells. Therefore, pathways localized in the vagus nerve constitute the afferent and efferent arms of the so-called «inflammatory reflex» that participates in negative feedback regulation of inflammation in peripheral tissues. Activation of efferent pathways of the vagus nerve significantly reduces tissue damage in several models of diseases in experimental animals. Clinical studies also indicate the importance of the vagus nerve in regulating inflammatory reactions in humans. It is suggested that alteration of the inflammatory reflex underlies the etiopathogenesis of diseases characterized by exaggerated production of pro-inflammatory mediators. Therefore, research into the inflammatory reflex may create the basis for developing new approaches in the treatment of diseases with inflammatory components.

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Moderate hypercapnia exerts beneficial effects on splanchnic energy metabolism during endotoxemia.

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Mer om den beskyttende effekten av hypercapni (økt CO2). Denne nevner at 60mmHg CO2 under bekteriell tarminfeksjon gjør at tarmene får mindre melkesyre og mindre ødeleggelse av vev.

http://www.ncbi.nlm.nih.gov/pubmed/19373455

Abstract

PURPOSE:

Low tidal volume ventilation and permissive hypercapnia are required in patients with sepsis complicated by ARDS. The effects of hypercapnia on tissue oxidative metabolism in this setting are unknown. We therefore determined the effects ofmoderate hypercapnia on markers of systemic and splanchnic oxidative metabolism in an animal model of endotoxemia.

METHODS:

Anesthetized rats maintained at a PaCO(2) of 30, 40 or 60 mmHg were challenged with endotoxin. A control group (PaCO(2) 40 mmHg) received isotonic saline. Hemodynamic variables, arterial lactate, pyruvate, and ketone bodies were measured at baseline and after 4 h. Tissue adenosine triphosphate (ATP) and lactate were measured in the small intestine and the liver after 4 h.

RESULTS:

Endotoxin resulted in low cardiac output, increased lactate/pyruvate ratio and decreased ketone body ratio. These changes were not influenced by hypercapnia, but were more severe with hypocapnia. In the liver, ATP decreased and lactate increased independently from PaCO(2) after endotoxin. In contrast, the drop of ATP and the rise in lactate triggered by endotoxin in the intestine were prevented by hypercapnia.

CONCLUSIONS:

During endotoxemia in rats, moderate hypercapnia prevents the deterioration of tissue energetics in the intestine.