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Posts Tagged ‘inflammation’

28 September 2013 20 Scientific Reasons to Start Meditating Today

September 11, 2013
by Emma M. Seppala, Ph.D.
Psychology Today

New research shows meditation boosts your health, happiness, and success!

I started meditating soon after 9/11. I was living in Manhattan, an already chaotic place, at an extremely chaotic time. I realized I had no control over my external environment. But the one place I did have a say over was my mind, through meditation. When I started meditating, I did not realize it would also make me healthier, happier, and more successful. Having witnessed the benefits, I devoted my PhD research at Stanford to studying the impact of meditation. I saw people from diverse backgrounds from college students to combat veterans benefit. In the last 10 years, hundreds of studies have been released. Here are 20 scientifically-validated reasons you might want to get on the bandwagon today:

It Boosts Your HEALTH

1 – Increases immune function (See here and here)

2 – Decreases Pain (see here)

3 – Decreases Inflammation at the Cellular Level (See here and here and here)

It Boosts Your HAPPINESS

4 – Increases Positive Emotion (here and here)

5 – Decreases Depression (see here)

6 – Decreases Anxiety (see here and here and here)

7 – Decreases Stress (see here and  here)

It Boosts Your SOCIAL LIFE

Think meditation is a solitary activity? It may be (unless you meditate in a group which many do!) but it actually increases your sense of connection to others:

8 – Increases social connection & emotional intelligence (see here and – by yours truly – here)

9 – Makes you more compassionate (see here and here and here)

10 – Makes you feel less lonely (see here)

It Boosts Your Self-Control

11 – Improves your ability to regulate your emotions (see here) (Ever flown off the handle or not been able to quiet your mind? Here’s the key)

12 – Improves your ability to introspect (see here & for why this is crucial see this post)

It Changes Your BRAIN (for the better)

13 – Increases grey matter (see here)

14 – Increases volume in areas related to emotion regulation, positive emotions & self-control (see here and here)

15 – Increases cortical thickness in areas related to paying attention (see here)

It Improves Your Productivity (yup, by doing nothing)

16 – Increases your focus & attention (see here and here and here and here)

17 – Improves your ability to multitask (see here and here)

18 – Improves your memory (see here)

19 – Improves your ability to be creative & think outside the box (see research by J. Schooler)

20. It Makes You WISE(R)

It gives you perspective: By observing your mind, you realize you don’t have to be slave to it. You realize it throws tantrums, gets grumpy,jealous, happy and sad but that it doesn’t have to run you. Meditation is quite simply mental hygiene: clear out the junk, tune your talents, and get in touch with yourself. Think about it, you shower every day and clean your body, but have you ever showered your mind? As a consequence, you’ll feel more clear and see thing with greater perspective. “The quality of our life depends on the quality of our mind,” writes Sri Sri Ravi Shankar. We can’t control what happens on the outside but we do have a say over the quality of our mind. No matter what’s going on, if your mind is ok, everything is ok. Right now.

It Keeps You Real

Once you get to know your mind, you start to own your stuff and become more authentic, maybe even humble. You realize the stories and soap operas your mind puts you through and you gain some perspective on them. You realize most of us are caught up in a mind-drama and become more compassionate towards others.

 

15 June 2013 Activating the Vagus Nerve

by Angela Savitri Petersen
Rising Life Media
25 October 2012
WHAT IS THE VAGUS NERVE?
The 10th of the cranial nerves, it is often called the “Nerve of compassion” because when it’s active, it helps create the “warm-fuzzies” that we feel in our chest when we get a hug or are moved by something…

The vagus nerve is a bundle of nerves that originates in the top of the spinal cord. It activates different organs throughout the body (such as the heart, lungs, liver and digestive organs). When active, it is likely to produce that feeling of warm expansion in the chest—for example, when we are moved by someone’s goodness or when we appreciate a beautiful piece of music.

Neuroscientist Stephen W. Porges of the University of Illinois at Chicago long ago argued that the vagus nerve is [the nerve of compassion] (of course, it serves many other functions as well). Several reasons justify this claim. The vagus nerve is thought to stimulate certain muscles in the vocal chamber, enabling communication. It reduces heart rate. Very new science suggests that it may be closely connected to receptor networks for oxytocin, a neurotransmitter involved in trust and maternal bonding.

Arizona State University psychologist Nancy Eisenberg has found that children with high-baseline vagus nerve activity are more cooperative and likely to give. This area of study is the beginning of a fascinating new argument about altruism: that a branch of our nervous system evolved to support such behavior.

STRESS & THE VAGUS NERVE

Your body’s levels of stress hormones are regulated by the autonomic nervous system (ANS) [3]. The ANS has two components that balance each other, the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS).

The SNS turns up your nervous system. It helps us handle what we perceive to be emergencies and is in charge of the flight-or-fight response.

The PNS turns down the nervous system and helps us to be calm. It promotes relaxation, rest, sleep, and drowsiness by slowing our heart rate, slowing our breathing, constricts the pupils of our eyes, increases the production of saliva in our mouth, and so forth.

The vagus nerve is the nerve that comes from the brain and controls the parasympathetic nervous system, which controls your relaxation response. And this nervous system uses the neurotransmitter, acetylcholine. If your brain cannot communicate with your diaphragm via the release of acetylcholine from the vagus nerve (for example, impaired by botulinum toxin), then you will stop breathing and die[6].

Acetylcholine is responsible for learning and memory. It is also calming and relaxing, which is used by vagus nerve to send messages of peace and relaxation throughout your body. New research has found that acetylcholine is a major brake on inflammation in the body [4]. In other words, stimulating your vagus nerve sends acetylcholine throughout your body, not only relaxing you but also turning down the fires of inflammation which is related to the negative effects from stress[1].

Exciting new research has also linked the vagus nerve to improved neurogenesis, increased BDNF output (brain-derived neurotrophic factor is like super fertilizer for your brain cells) and repair of brain tissue, and to actual regeneration throughout the body.

HEALTH, LONGEVITY & AGING

As you get older, your immune system produces more inflammatory molecules, and your nervous system turns on the stress response, promoting system breakdown and aging.

That’s not just talk. It’s backed by scientific studies.

For example, Kevin Tracey, the director of the Feinstein Institute for Medical Research, discovered how the brain controls the immune system through a direct nerve-based connection.

He describes this as the inflammatory reflex (i). Simply put, it is the way the immune system responds to the mind.

Let me explain.

You immune system is controlled by a nerve call the vagus nerve.

But this isn’t just any nerve.

It is the most important nerve coming from the brain and travels to all the major organs.

And you can activate this nerve — through relaxation, meditation, and other ancient practices, such as the Mayan system of Light Language, combined with Vagus Nerve Activation Techniques given recently by the Group & Steve Rother, the Vagus Nerve can be activated and worked with energetically through geometry, frequency, color, and light.

What’s the benefit of that?

Well, by activating the vagus nerve, you can control your immune cells, reduce inflammation, and even prevent disease and aging!

It’s true. By creating positive brain states — as meditation masters have done for centuries — you can switch on the vagus nerve and control inflammation.

You can actually control your gene function by this method. Activate the vagus nerve, and you can switch on the genes that help control inflammation. Inflammation is one of the central factors of disease and aging.

CELLULAR REGENERATION

Even more fascinating was the discovery that our bodies can regenerate at any age.

Diane Krause, MD, PhD, from Yale University discovered that our own innate adult stem cells (cells that can turn into any cell in the body from our bone marrow) could be transformed into liver, bowel, lung, and skin cells. (ii)

This is a phenomenal breakthrough.

Here’s why.

It means that we have the power to create new cells and renew our own organs and tissues at any age.

And how are these stem cells controlled?

You guessed it: the vagus nerve.

For example, Theise et al. [5] have found that stems cells are directly connected to the vagus nerve. Activating the vagus nerve can stimulate stem cells to produce new cells and repair and rebuild your own organs.

So relaxation — a state of calm, peace, and stillness – can activate the vagus nerve.

And the vagus nerve, in turn, activates your stem cells to regenerate and renew your tissues and organs.

RELAXATION & MEDITATION

Scientists have even shown how meditation makes the brain bigger and better.

They’ve mapped out the brain function of “professionalmeditators” by bringing Tibetan lamas trained in concentration and mental control into the laboratory.

The result? They found higher levels of gamma brain waves and thicker brain cortexes (the areas associated with higher brain function) in meditators. (iii)

Relaxation can have other powerful effects on our biology.

In biology, being a complex system that can adapt to its environment and that is resilient and flexible is critical to health.

The same is true for us.

The more complex and resilient we are, the healthier we are.

Take, for example, our heartbeat.

Its complexity is called heart rate variability (HRV) or beat-to-beat variability. The more complex your HRV, the healthier you are. The least complex heart rate is the worst — a flat line.

So what does this have to do with relaxation?

The HRV is also controlled by the vagus nerve.

As you can see, turning on the relaxation response and activating that vagus nerve is critical to health.

Activating the Vagus Nerve Will:

* Reduce inflammation

* Help regenerate your organs and cells by activating stem cells

* Increase your heart rate variability

* Thicken your brain (which normally shrinks with aging).

* Boost immune function

* Modulate your nervous system

* Reduce depression and stress

* Enhance performance

* Improve your quality of life

Not bad for just learning to chill out!

COMPASSION & DNA

Elizabeth Blackburn, PhD, who discovered telomeres, explained that, ultimately, they become so short that the end of our DNA unravels and we can no longer replicate our cells, so they die.

Remarkably, mental stress produces a more rapid shortening of the telomeres — and leads to faster aging.

What’s even more remarkable?

In a study of caregivers of sick patients, the health of the caregivers’ telomeres was determined by their attitude!

It sounds impossible, but it’s true.

The caregivers who felt the care to be a burden had shorter telomeres, while those who saw their work as an opportunity to be compassionate had no shortening. (iv)

The Dalai Lama said that the seat of compassion is actually biological and — necessary for survival.

Perhaps the development of compassion and wisdom in coping with unfavorable life conditions is the true key to longevity.

It just may be that working to understand our true nature through the cultivation of our minds and hearts with positive practices like meditation or similar techniques is critical to health and longevity.

The ways we can change our bodies through changing our minds is not longer a theory.

There is a new scientific language to understand how the qualities of the mind control the body through effects on the vagus nerve, immune cells, stem cells, telomeres, DNA, and more.

Remember, your body has all the resources and infinitely adaptable systems to self-regulate, repair, regenerate, and thrive.

You simply have to learn how to work with your body, rather than against it. Then you can have a healthy, thriving life – and live out your full lifespan, which can be as high as 120+ years!

LOVE

But here’s something even cooler – the research that Dacher Ketlner, director of the Social Interaction Laboratory at the University of California, Berkeley is doing shows that stimulating that vagus nerve is not only good for you – it’s good for the planet!

“Our research and that of other scientists suggest that activation of the vagus nerve is associated with feelings of caretaking and the ethical intuition that humans from different social groups (even adversarial ones) share a common humanity. People who have high vagus nerve activation in a resting state, we have found, are prone to feeling emotions that promote altruism – compassion, gratitude, love and happiness.”

There you go. Do it for love.

 

references:

https://sites.google.com/site/stanleyguansite/health/health-tips/breathe-deeply-to-activate-vagus-nerve

http://tkcollier.wordpress.com/2006/10/05/how-the-dalai-lama-can-help-you-live-to-120/

http://www.subtleyoga.com/220/11

http://www.scientificamerican.com/article.cfm?id=forget-survival-of-the-fittest

 

 

1 November 2012 Éiriú Eolas in Edmonton – November 2012

15 August 2012 Meditation helps older adults battle loneliness and illness, study says

By Stephanie O’Neill
 Aug 13, 2012
Link to original

Joern Pollex/Getty Images – A new study shows that repeat meditation exercises could show measurable reductions in gene inflammation and loneliness in the elderly.

Loneliness in older people is linked to an increased risk for serious illnesses, such as Alzheimer’s disease, heart disease and depression.

It’s an issue that’s long concerned health workers who deal with older patients, but a new UCLA study of 40 people, aged 55-85, suggests a solution may not be hard to come by.

The eight-week study trained subjects in a simple meditation program, which focused mainly on paying attention to the present and refusing to dwell in the past. Those patients who practiced the meditation exercise showed measurable reductions in loneliness and in gene inflammation (measured by blood tests).

Meditation’s effect on reducing gene inflammation is an especially important finding, researchers say, because chronic gene inflammation is known to promote a number of physical diseases and psychological disorders.

The study appears in the current online edition of the journal Brain, Behavior & Immunity.

 

21 May 2012 Meditation is Good for Your Brain

Bob Curley
May 15, 2012
Well-Being Wire

 

Photo © Denise Cross via Flickr

People who meditate for many years seem to enjoy a variety of cognitive benefits, including greater neuroplasticity (the ability of the brain to make physiological changes) and more white and dark brain matter, the New York Times reported May 8.

Research also has shown that meditation may help lower the risk of death from coronary artery disease — possibly by reducing stress hormones and inflammation — and that long-term meditators have more folding in their cerebral cortex, which could mean more neurons firing in their brains, resulting in greater cognitive capacity.

“We used to believe that when you were born, your brain would grow and reach a peak in the early 20s and then start shrinking,” says Eileen Luders of UCLA, author of the latter study. “It was thought there was nothing we could do to change that.” Experts now think that the mental challenges presented by meditation can help the aging brain. “People ask, ‘What do you do? Just sit there with your eyes closed?’ It’s actually hard work, because you have to make a constant mental effort,” explains Luders.

Other studies have concluded that meditating is good for your emotional health and could even reduce healthcare costs.

Luders’ study was published in February 2012 in the journal Frontiers in Human Neuroscience.

21 February 2012 Éiriú Eolas in Edmonton – March 2012

11 January 2012 Compassion, the vagus nerve and how to live longer

by David R. Hamilton PHD
Patterns of Experience:Body Therapies and Healing Trauma
September 23, 2010

The Philosopher’s Stone Has Been Found…It’s Inside You

For centuries learned people have searched for the mystical philosopher’s stone, believed to be the elixir of life and give immortality to he or she who owns it.

But could it be that the philosopher’s stone is not so much a stone but an attitude?

A groundbreaking piece of research by Kevin Tracey, director of the Feinstein Institute and Professor and President of the Elmezzi graduate school of molecular medicine in Manhasset, New York, has revealed how the nervous system (the vagus nerve) controls inflammation in the body, now known as ‘The Inflammatory Reflex’. Inflammation is one of the major contributors to aging of the body and plays a key role in illness and disease.

Most people think of inflammation as the swelling and redness after a cut. This inflammation is a vital part of healing and helps to ensure that nutrient-rich blood is drawn to the site of injury to help facilitate healing. But it turns out that if it wasn’t for the vagus nerve  – the longest nerve in the body that runs from the top of the brainstream, through the face, throat, chest, heart, the GI tract, all major organs, and even over certain immune cells – inflammation from a small cut would typically spill out into the bloodstream and lead to septic shock and multiple organ failure.

The vagus nerve is the brake on inflammation throughout the body. Once the vagus nerve senses that there are enough inflammatory substances (the chemicals of inflammation) following an injury it sends a signal to the immune cells that make those chemicals and tells them to turn off production.

The vagus nerve puts the brakes on inflammation in much the same way that you might apply the brake in your car when you’re travelling a little over the speed limit.

The vagus nerve is highly important because inflammation doesn’t only arise in response to injury; it is also a side effect of unhealthy lifestyle factors – like poor diet, drinking, stress, etc. It plays a key role in heart disease, some cancers, and in fact it is involved in just about every serious disease we know of in western medicine.

Indeed, it is one the ‘Major Agers’, which are phenomena that most cause aging. So much so, in fact, that many gerontologists believe that if science could develop a powerful body-wide anti-inflammatory drug then the average person would live until they were around 150 years old.

But we now know that the vagus nerve is our natural anti-inflammatory nerve. Maybe the wonder drug that pharmaceutical companies are currently searching for isn’t necessary. Maybe all we need to do is train our vagus nerves in much the same way that we train at a gym. Is this possible?

It seems that people have different vagus nerve activity, or what is sometimes called, ‘vagal tone’. Think of it like muscle tone. A person who exercises regularly might enjoy good muscle tone and similarly a person who exercises or does meditation, yoga or tai chi, might enjoy good vascular tone. Vagal tone is used in a similar capacity to indicate power, activity, health etc of the vagus nerve.

Some people’s nervous systems, then, are more efficient at keeping inflammation at bay, just as different people have different immune system robustness. Some are good at keeping them free of illness and some aren’t quite so good.

Recently, a link has been identified between the vagus nerve and compassion. In some studies people who are most compassionate were found to have the highest vagal tone, and similarly the reverse is also true. People who have the highest vagal tone tend to be the most compassionate. In some of this research Dacher Keltner, psychology professor at Berkley, calls these people ‘vagal superstars’. According to much of his research, the association between the vagus nerve and compassion is very strong.

So could training ourselves to be more compassionate actually train the vagus nerve and reduce inflammation in the body? Scientists have indeed recently studied the link between compassion and inflammation.

In a 2009 study, scientists at Emory University School of Medicine, trained 33 people in a compassion meditation, which involved the structured generation of feelings of compassion on a daily basis, and compared them with a group of 28 people who didn’t do the meditation. After 6 weeks those who did the compassion meditation had much lower levels of inflammation in their bodies than those who didn’t.

Since the vagus nerve is the primary brake on inflammation and compassion is correlated with the vagus nerve, it makes sense that compassion actually reduces inflammation in the body.

Could it be that the philosopher’s stone that many have searched long and hard for has always been right in front of our eyes? In fact, it is not so much in front of our eyes but in our hearts? Could it be that simple? History has taught us that things usually are that simple. Maybe it’s called the philosopher’s stone because it takes a philosopher to consider compassion to be the elixir of life. Perhaps humanity has only just reached a point of spiritual maturity to even contemplate such a thing.

So why is it that compassionate people everywhere aren’t living until they’re over a hundred? Well, we counter the effects of it with other lifestyle choices we make – the unhealthy foods we eat, the toxins and stimulants we take into our bodies, our unhealthy habits like smoking and drinking (too much), not exercising regularly, and also our mental emotional stresses of life. Many of us are so stressed that we neutralise the effects of most of our healthy habits. Perhaps, the journey now is to learn to treat our bodies and minds well.

The new healthy formula:

Eat well, sleep well, exercise well, think well, and show people that you care!

Perhaps this formula is the mystical philosopher’s stone. Maybe the stone is not a stone, but a Way, the philosopher’s Way.

And that way is compassion.

References:

For Kevin Tracey’s discovery of the inflammatory reflex, see K. J. Tracey, ‘The inflammatory reflex’, Nature 420, 2002, 853–9; also H. Wang, et al., ‘Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation’, Nature 421, 2003, 384–8

For the link between the vagus nerve and compassion, see Dacher Keltner, Born to Be Good: The Science of a Meaningful Life, Norton, New York, 2009

For the study of compassion meditation and inflammation, see: T. W. W. Pace, L. T. Negi, D. D. Adame, S. P. Cole, T. I. Sivillia, T. D. Brown, M. J. Issa and C. L. Raison, ‘Effect of compassion meditation on neuroendocrine, innate immune and behavioural responses to psychosocial stress’, Psychoneuroendocrinology 34, 2009, 87–98

For a good summary of the compassion-vagus nerve-inflammation link, see David R Hamilton PhD, Why Kindness is Good for You, Hay House, London, 2010.

24 September 2011 Body’s defences not immune to brain control

Chris Smith 15th Sep 2011
The Naked Scientist

A neurochemical circuit that enables the brain to control the immune system has Human lymphocytebeen revealed for the first time.

Scientists have known for many years of the powerful connection between the psyche and the functioning of the immune system, although the neurological underpinnings of the relationship have remained shrouded in mystery.

Now a team at the Feinstein Institute for Medical Research in New York and the Karolinska Institute in Stockholm, writing in the journal Science, have unravelled the workings of the communication system linking the nervous system and immunity. And what’s really surprising is that immune cells themselves act as go-betweens to transmit chemical messages from nerve cells to other immune signalling cells.

Previous work conducted by Kevin Tracey, the senior author in the present study, had shown that stimulating the Vagus nerve, which runs from the brainstem to supply tissues in many parts of the body, could stop the immune system pumping out inflammatory signals. The signal responsible seemed to be a well-known nerve transmitter chemical called acetylcholine. But the wrinkle in the story was that the Vagus nerve did not appear to be producing it!

Now, by studying the spleens of experimental mice, the team have solved the mystery. White blood cells in the spleen called CD4 lymphocytes, when activated by inflammatory processes, become sensitive to the nerve transmitter chemical noradrenaline, secreted in the spleen by the splenic branch of the Vagus nerve. The CD4 lymphocytes themselves then secrete acetyl choline, which in turn switches off the production of inflammatory chemicals by other nearby cells.

The team proved this by carrying out experiments in mice lacking their own CD4 cells; these animals did not switch off the supply of inflammatory mediators when their Vagus nerves were stimulated. But when activated CD4 cells were transfused into the animals from donor mice, they immediately began to churn out acetylcholine, inhibiting the inflammatory process. Switching off the ChAT gene, which makes acetylcholine in these cells, also prevented any response.

Importantly, as the team point out in their paper, the regulatory system they have discovered is not confined to the spleen because the same sorts of CD4 lymphocytes are present throughout the body, particularly in lymph glands and specialised lymphoid tissue in the intestine called Peyer’s Patches. This means that the system almost certainly plays a major role in controlling inflammation throughout the body and manipulating it could hold the key to controlling autoimmune and other related disorders.

9 August 2011 Éiriú Eolas in Edmonton – September 2011

19 July 2011 Role of the Vagus Nerve at the Neural-Immune Interface

Friday, 20 August 2010
K Ondicova & B Mravec
Ja Teline

timthumbEvidence shows that the central nervous system monitors and modulates the activity of both circulating and tissue immune cells via the neuroendocrine system and autonomic nerves. Furthermore, findings over the last decade have demonstrated that the vagus nerve represents an important bi-directional link between the brain and immune system.

Afferent vagal pathways transmit information to the brain related to peripheral inflammation so as to participate in the activation of adaptive reactions, including fever and sickness behavior. On the other side, efferent vagal pathways inhibit the synthesis and release of pro-inflammatory cytokines by peripheral immune cells. Because activation of afferent vagal pathways by immune stimuli leads to suppression of immune reactions, the term inflammatory reflex was introduced. The inflammatory reflex adjusts the intensity and duration of inflammatory reactions according to actual needs, thus protecting an organism from tissue damage induced by excessive inflammation. Both experimental and clinical studies suggest that inappropriate activation of the inflammatory reflex participates in the development of diseases characterized by excessive production of cytokines.’, ‘

Introduction

Regulation of immune system activity by the central nervous system plays an important role in both physiological and pathological conditions. This is shown by several studies demonstrating that the vagus nerve represents one of the key brain structures participating in monitoring immune system activity. The vagus nerve is involved in the transmission of information from inflamed peripheral tissues to the brain, and participates in both homeostatic and behavioral adaptation reactions, including the induction of fever and sickness behavior. Vagal afferent pathways are activated by immune stimuli either directly or indirectly via vagal paraganglia cells. These paraganglia cells possess receptors for immune signaling molecules (e.g. IL-1) and transmit signals from immune cells to the afferent vagal pathways. The importance of afferent vagal pathways in the transmission of immune-related signals is demonstrated by the inhibitory effect of subdiaphragmatic vagotomy on the development of fever responses induced by intraperitoneal injection of low doses of IL-1beta [1,2].

Although the role of afferent vagal pathways in the transmission of immune signals to the brain has been demonstrated over time, the role of efferent vagal pathways in the modulation of immune cells activity has only recently been shown. This occurred during the search for a new compound for the treatment of excessive inflammatory reactions (e.g. sepsis) with the synthesis of CNI-1493 (tetravalent guanyl-hydrazone). This compound was shown to inhibit the release of pro-inflammatory cytokines from macrophages, significantly prolonging the survival of animals in experimental models of sepsis induced by endotoxin [3]. Moreover, it was found that application of CNI-1493 increased the activity of efferent vagal pathways and that its anti-inflammatory effects were blocked by vagotomy [4]. Later studies demonstrated that CNI-1493 inhibits both the synthesis and release of pro-inflammatory cytokines from immune cells through activation of efferent vagal pathways at the level of central nervous system. Later, this inhibitory effect of the vagus nerve on immune cells activity was found to be mediated by acetylcholine, and the term cholinergic anti-inflammatory pathway was introduced [5,6].

Inflammatory reflex and cholinergic anti-inflammatory pathway

The synthesis and release of cytokines represents one of the most basic activities during immune reactions. However, inappropriate cytokine synthesis may stimulate excessive inflammatory reactions causing damage to peripheral tissues and organs. It is therefore not surprising that organisms have several mechanisms regulating the intensity of inflammation, including the inflammatory reflex of the vagus nerve.

The pathways of the vagus nerve that participate in the monitoring and modulation of immune reactions in the periphery of an organism make up the sensory arm of the inflammatory reflex. This “arm” consists of afferent vagal pathways transmitting signals to the brain generated in inflammation-affected tissues. The motor arm of this reflex consists of the efferent vagal pathways that constitute the cholinergic anti-inflammatory pathway (Fig. 1).

Role-of-the-Vagus-Nerve

Fig. 1 | Inflammatory reflex of the vagus nerve
Infection or injury induces production of cytokines by immune cells. Stimulation of paraganglia cells by tissue or circulating cytokines leads to activation of afferent vagal pathways. Immune-related signals are transmitted to the nucleus of the solitary tract (NTS). Consequently, the activated dorsal motor nucleus of the vagus may inhibit immune cell activity either directly or indirectly by activation of sympathetic postganglionic neurons innervating the spleen.

As a result of activating the motor arm, acetylcholine released from vagal nerve endings potently inhibits the production of cytokines by macrophages, thus protecting peripheral tissues from inflammatory injury [7]. As a result of these observations, it was concluded that the inflammatory reflex represents a crucial neural mechanism controlling the synthesis and release of cytokines [5,6].

Either pharmacological or electrical stimulation of efferent vagal pathways significantly inhibits the release of TNF-alpha in animals given a lethal dose of endotoxin. Furthermore, studies have shown that stimulation of the efferent pathways of the vagus nerve has beneficial effects such as inhibiting the development of pathological consequences in animal models of ischemia-reperfusion injury, myocardial ischemia, hemorrhagic shock, shock induced by occlusion of splanchnic artery, ileus, experimental arthritis, pancreatitis, and burn-induced organ dysfunction [8-12].

The inhibition of cytokine biosynthesis by the cholinergic anti-inflammatory pathway is caused by cholinergic neurotransmission acting on alpha7 subtype acetylcholine receptors (alpha7nAChR) located on macrophages and other cytokine synthesizing cells [13,14]. As evidence of this, both direct electrical stimulation of the vagus nerve and the application of alpha7nAChR agonists inhibit synthesis of TNF-alpha, IL-1beta, IL-6, IL-8, and HMGB1. This binding of acetylcholine and acetylcholine analogues to the alpha7nAChR of immune cells also induces a reduction in the nuclear translocation of NF-kappaB, a pro-inflammatory gene regulatory protein. Furthermore, as other immune cells, including lymphocytes and microglia express alpha7nAChR, this suggests that the cholinergic anti-inflammatory pathway may have wide effects across various immune cells [14]. This assumption is supported by the finding of increased proliferation and cytokine secretion by CD4+ T cells in mice that have undergone subdiaphragmatic vagotomy. Furthermore, administration of nicotine restored the reactivity of immune cells in these animals, while administration of nicotine receptor antagonists induced an effect similar to subdiaphragmatic vagotomy. These findings suggest that efferent vagal pathways modulate a tonic inhibition of macrophage and T cell activity. Regardless of the whatever else is learned about this system, it can be agreed that the involvement of the vagus nerve in regulation of immune function is highly complex [15].

The role of the spleen

The spleen plays a key role in the regulation of immune function by the vagus nerve. During their passage through the spleen, circulating immune cells are exposed to vagus nerve endings [16]. Moreover, as the spleen is a prominent source of circulating TNF-alpha during endotoxemia and stimulation of the vagus nerve inhibits endotoxin-induced increases in plasma TNF-alpha, it is possible that lymphoid compartments of the spleen represent a target for vagal anti-inflammatory action [17]. However, the role of direct vagal fibers innervating the spleen in the regulation of inflammation remains questionable. In fact, anatomical and physiological studies indicate that the vagus nerve modulates the activity of immune cells within the spleen indirectly via activation of sympathetic postganglionic neurons localized in the coeliac ganglia. It is therefore possible that the vagus nerve modulates immune system activity in the spleen indirectly through regulation of norepinephrine release from sympathetic nerve endings [18].

The importance of cholinergic anti-inflammatory pathway in human medicine

The majority of data related to anti-inflammatory effects of the vagus nerve have been obtained in animal studies. However, several clinical studies on the role of cholinergic anti-inflammatory pathway in humans were published recently. In one study administration of nicotine before activation of the immune system by lipopolysaccharide attenuated increases in body temperature and increased plasma IL-10 and corticosterone levels [19].
Anti-inflammatory effect of the vagus nerve may explain several clinical findings. For example, increased plasma levels of C reactive protein, IL-6, and TNF-alpha were found in patients with insulin resistance, diabetes mellitus type 2, hypertension, hyperlipidemia, metabolic syndrome, and Alzheimer’s disease; all conditions characterized by low-grade inflammation. Interestingly, increased plasma and tissue activity of butyrylcholinesterase and acetylcholinesterase were found in these patients. Since increased activation of these enzymes leads to decreased transmission of cholinergic signals and acetylcholine represents a key molecule in the cholinergic anti-inflammatory pathway, increased degradation of acetylcholine may participate in exaggerated inflammatory reactions [20]. Moreover, the beneficial effects of nicotine treatment in patients with ulcerative colitis suggests that inappropriate activity of cholinergic anti-inflammatory pathway may participate in its development as well [18].

Several methods can be used to stimulate the cholinergic anti-inflammatory pathway. For example, it is possible to activate the afferent and/or efferent arm of inflammatory reflex by stimulating the cholinergic anti-inflammatory pathway at the central level by administration of muscarine receptor agonists, ACTH, ghrelin, or centrally acting acetylcholinesterase inhibitors [5,21,22]. Ingestion of polyunsaturated fatty acids also increases vagal anti-inflammatory activity [23] and therefore may represent a potent and simple therapeutic method for the treatment of inflammatory diseases. Moreover, decreased pro-inflammatory immune cell responses were found in patients with epilepsy treated by electrical stimulation of the vagus nerve [24].

Based on published data it is suggested that activation of cholinergic anti-inflammatory pathway may represent a useful therapeutic approach. However, exaggerated activation of the cholinergic anti-inflammatory pathway may excessively suppress immune function, thereby inducing unfavorable consequences [25]. Therefore, it is necessary to consider two consequences of activating the cholinergic-anti-inflammatory pathway: 1) inhibition of inflammation that has beneficial effects during septic or hemorrhagic shock, ischemia-reperfusion injury, and other situations related to excessive stimulation of immune functions; 2) inhibition of immune functions may negatively influence defense mechanisms against invading pathogens, such as during the early stages of bacterial pancreatitis. Furthermore, the consequences of activating the cholinergic anti-inflammatory pathway may depend on not only the pathological situation, but the stage of disease as well. This is seen during the early stages of inflammatory reaction where induced activation of the cholinergic anti-inflammatory pathway will produce negative effects; while in later stages it may be beneficial, protecting organisms from injury induced by excessive inflammatory reaction.

Conclusions

Animal studies have unambiguously shown that the vagus nerve plays an important role in the regulation of immune reactions in various animal models of inflammatory diseases. While several studies in humans also indicate the importance of the vagus nerve in the regulation of immune function, it is necessary to take into consideration the fact that these studies used mainly ex vivo approaches, using heart rate variability as a marker of cholinergic anti-inflammatory pathway activity. Therefore, further experimental and clinical studies will be necessary to elucidate the role of the vagus nerve in the modulation of inflammatory reactions in humans.

Acknowledgments
This work was supported by the Slovak Research and Development Agency under the contract No. APVV-0045-06, VEGA grants (1/0258/10, 1/0260/10, 2/0010/09) and European Regional Development Fund Research and Development Grant No. NFP26240120024.

 

K Ondicova // Institute of Pathophysiology, Faculty of Medicine, Comenius University, 811 08 Bratislava
B Mravec // Institute of Experimental Endocrinology, Slovak Academy of Sciences, 833 06 Bratislava, Slovak Republic

Nonstandard Abbreviations: alpha7nAChR, alpha7 subtype acetylcholine receptors; HMGB1, high-mobility group box 1; IL, interleukin; LPS, lipopolysaccharide; TNF-alpha, tumor necrosis factor alpha

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