“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 • 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 Shock • 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 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
Anti-Inflammatory Responses Normally Inhibit Inflammation Nature. 2002;420:853-859 Slow, distributed throughout body and dependent on concentration gradients.
Communication Between Immune and Nervous 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 • 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 Nature. 2002;420:853-859
Wiring of the Inflammatory Reflex 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 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 -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.
-Bungarotoxin-binding nicotinic receptors are clustered on the surface of macrophages. Nature. 2003;421:384-388
Increased cytokine production in 7 subunit-deficient mice during endotoxemia. Nature. 2003;421:384-388
Vagus nerve stimulation does not inhibit TNF production in 7subunit deficient mice. Nature. 2003;421:384-388
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…
Targeting Therapies to the Cholinergic Anti-Inflammatory Pathway Nature. 2002;420:853-859