Patients who develop sepsis and multiple organ failure after surgery or trauma face significant morbidity and mortality. Our approach since originally synthesizing the macrophage-deactivating, low molecular weight, multivalent guanylhydrazone CN1-1493, has been to use this compound as a tool to probe physiological echanisms that inhibit systemic inflammatory mediator responses. Studies of CNI-1493 mechanism of action in animal models of endotoxemia and sepsis unexpectedly revealed a neural mechanism to inhibit systemic inflammation through vagus nerve stimulation. These surprising observations revealed a previously unrecognized neuroimmune mechanism now termed the """"""""cholinergic anti-inflammatory pathway,"""""""" which rapidly deactivates macrophages. This opened a new avenue for investigating regulation of systemic inflammation that we have pursued. Preliminary Results show that electrical stimulation of the vagus nerve specifically inhibits macrophage activation, prevents TNF synthesis in liver and heart, and significantly attenuates the systemic inflammatory response to endotoxemia. Vagus nerve stimulators are widely used in the treatment of epilepsy (they are quite safe) but their impact on immune responses was previously unknown. This application now seeks funding to pursue this line of basic physiological investigation, and to define the impact of the cholinergic anti-inflammatory pathway on regulation of systemic and organ-specific macrophage activation in vivo in standard animal models of endotoxemia and sepsis.
Specific Aim 1 will establish the physiological basis for the anti-inflammatory action of vagus nerve regulation of macrophage activation in specific organs by stimulating and selectively denervating the vagus nerve input to major macrophage-containing organs in the context of 1) endotoxemia and 2) sepsis.
Specific Aim 2 will assess the influence of vagus nerve stimulation on early and late systemic inflammatory cytokine responses in a clinically relevant model of hemorrhagic shock followed by sepsis. The proposed approach will address whether therapeutic, cytokine-suppressing utilization of vagus nerve stimulators can reduce mortality; or indeed cause the opposite effect by increasing susceptibility to septic complications in the traumatized, shocked host. The mechanistic insights derived from understanding how vagus nerve stimulation deactivates macrophages, and whether this strategy can be used in the milieu of endotoxemia or post-traumatic sepsis, are critical for the design of future therapies targeting the pathobiology of sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057226-07
Application #
7057797
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
1999-09-30
Project End
2007-09-09
Budget Start
2006-05-01
Budget End
2007-09-09
Support Year
7
Fiscal Year
2006
Total Cost
$367,165
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Pavlov, Valentin A; Chavan, Sangeeta S; Tracey, Kevin J (2018) Molecular and Functional Neuroscience in Immunity. Annu Rev Immunol 36:783-812
Consolim-Colombo, Fernanda M; Sangaleti, Carine T; Costa, Fernando O et al. (2017) Galantamine alleviates inflammation and insulin resistance in patients with metabolic syndrome in a randomized trial. JCI Insight 2:
Pavlov, Valentin A; Tracey, Kevin J (2017) Neural regulation of immunity: molecular mechanisms and clinical translation. Nat Neurosci 20:156-166
Olofsson, Peder S; Steinberg, Benjamin E; Sobbi, Roozbeh et al. (2016) Blood pressure regulation by CD4(+) lymphocytes expressing choline acetyltransferase. Nat Biotechnol 34:1066-1071
Pavlov, Valentin A; Tracey, Kevin J (2015) Neural circuitry and immunity. Immunol Res 63:38-57
Silverman, Harold A; Dancho, Meghan; Regnier-Golanov, Angelique et al. (2015) Brain region-specific alterations in the gene expression of cytokines, immune cell markers and cholinergic system components during peripheral endotoxin-induced inflammation. Mol Med 20:601-11
Hanes, William M; Olofsson, Peder S; Kwan, Kevin et al. (2015) Galantamine Attenuates Type 1 Diabetes and Inhibits Anti-Insulin Antibodies in Nonobese Diabetic Mice. Mol Med 21:702-708
Rosas-Ballina, Mauricio; Vald├ęs-Ferrer, Sergio I; Dancho, Meghan E et al. (2015) Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation. Brain Behav Immun 44:19-27
Matteoli, Gianluca; Gomez-Pinilla, Pedro J; Nemethova, Andrea et al. (2014) A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen. Gut 63:938-48
Munyaka, Peris; Rabbi, Mohammad F; Pavlov, Valentin A et al. (2014) Central muscarinic cholinergic activation alters interaction between splenic dendritic cell and CD4+CD25- T cells in experimental colitis. PLoS One 9:e109272

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