Bridging the cns and immune system via the vagus nerve
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Bridging the CNS and Immune System via the Vagus Nerve. Jill Adamski.

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“The nervous system reflexively regulates the inflammatory response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible “hard-wired” neural systems.”

K. J. Tracey


Septic shock
Septic Shock response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible “hard-wired” neural systems.”

  • Caused by systemic microbial infection

  • Kills over 175,000 people each year in US

  • Incidence is increasing due to improved life support for high risk individuals, increasing invasive procedures and immunocompromised patients


Septic shock1
Septic Shock response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible “hard-wired” neural systems.”

  • Systemic vasodilatation (hypotension)

  • Diminished myocardial contractility

  • Widespread endothelial injury and activation, causing systemic leukocyte adhesion and pulmonary alveolar capillary damage (ARDS)

  • Activation of coagulation system (DIC)

  • Hypoperfusion results in multiorgan system failure (liver, kidneys, CNS, etc)

  • Unless underlying infection (LPS overload) is rapidly brought under control the patient usually dies.


Effects of septic shock can be reproduced by lps alone
Effects of Septic Shock can be Reproduced by LPS Alone response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible “hard-wired” neural systems.”

LPS

TNF

IL-1

IL6/IL-8

NO, PAF, etc.

Low Quantities

Mono/mac activation

Endo Activation

Complement Activation

Local Inflammation

Moderate Quantities

Brain- Fever

Liver- Acute phase reactants

Systemic Effects

High Quantities

Low cardiac output and peripheral resistance

Blood vessel injury, thrombosis, DIC

ARDS

Septic Shock


TNF- response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible “hard-wired” neural systems.”


Anti-Inflammatory Responses Normally Inhibit Inflammation response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible “hard-wired” neural systems.”

Nature. 2002;420:853-859

Slow, distributed throughout body and dependent on concentration gradients.


Communication between immune and nervous systems
Communication Between Immune and Nervous Systems response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible “hard-wired” neural systems.”

  • H-P-A responses after LPS administration… provided early evidence that inflam stimuli can activate anti-inflam signals from CNS

  • Common molecular basis for communication: neurons can make TNF and IL-1, cells of immune system can produce neuropepties, ACh, and other neurotransmitters.

  • Cholinergic Anti-Inflammatory Pathway


Autonomic nervous system
Autonomic Nervous System response in real time, just as it controls heart rate and other vital functions. The opportunity now exists to apply this insight to the treatment of inflammation through selective and reversible “hard-wired” neural systems.”

  • 2 principal divisions: Sympathetic and Parasympathetic

  • Controls visceral body functions and innervates glands (involuntary)

  • Continuously controls heart and respiratory rate, blood pressure, GI motility, body temp, and other constantly changing essential life functions

  • Normally subconscious, but can be put under conscious control from signals originating in the higher brain.

    • Subjects can be trained through biofeedback to decrease their heart rate by increasing parasympathetic outflow


Vagus Nerve Innervations - Acetylcholine is principle parasympathetic neurotransmitter

Parasympathetic

Stimulates digestion & motility

Stimulates urination

Airway constriction

Decreases HR

Constricts pupil

Erection/lubrication

* Reticuloendothelial System

*

*

*

*

*


Cholinergic Anti-Inflammatory Pathway parasympathetic neurotransmitter

Nature. 2002;420:853-859


Wiring of the Inflammatory Reflex parasympathetic neurotransmitter

E. Blalock (UAB)originally postulated that the immune system acts as a “6th sense” that detects microbial invasion and produces molecules that relay this info to the brain.

Nature. 2002;420:853-859


Diffusible vs. Neural Anti-Inflammatory Pathways parasympathetic neurotransmitter

Nature. 2002;420:853-859

Cholinergic anti-inflammatory pathway is discrete and localized in tissues where invasion and injury typically originate.


“Dovetail” between parasympathetic nervous system and the innate immune system is a nicotinic, -bungarotoxin-sensitive macrophage acetylcholine receptor

7

7

7

7

7

7


a the innate immune system is a nicotinic, -Bungarotoxin(a -BgTx) is a postsynaptic neurotoxin found in the venom of the Braided Krait snake (Bungarus Multictus). Like other neurotoxins it blocks neuromuscular transmission.


the innate immune system is a nicotinic, -Bungarotoxin-binding nicotinic receptors are clustered on the surface of macrophages.

Nature. 2003;421:384-388


Increased cytokine production in the innate immune system is a nicotinic, 7 subunit-deficient mice during endotoxemia.

Nature. 2003;421:384-388


Nature the innate immune system is a nicotinic, . 2003;421:384-388


Vagus nerve stimulation does not inhibit TNF production in the innate immune system is a nicotinic, 7subunit deficient mice.

Nature. 2003;421:384-388


Vagus nerve

Activation by direct electrical stimulation inhibits synthesis of TNF in liver, spleen, and heart, and attenuates serum concentrations of TNF during endotoxemia

Vagotomy significantly exacerbates TNF responses to inflammatory stimuli and sensitizes animals to the lethal effects of endotoxin

Vagus Nerve…



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