Trauma and surgery patients who survive an initial bout of hemorrhagic shock frequently develop complications related to infection. The mortality of sepsis among critically ill traumatized and surgical patients is extremely high, largely because the underlying disease pathogenesis is incompletely understood. In an effort to develop a therapeutic strategy for post-trumatic sepsis, the PI designed and synthesized a tetravalent guanylhydrazone (""""""""TG,"""""""" or """"""""CNI-1493"""""""") inhibitor of macrophage activation. CNI-1493 effectively prevents the synthesis of multiple proinflammatory mediators (e.g. TNF, IL-1 and NO) that are known to contribute to the lethality of sepsis by preventing the phosphorylation of p38 MAP kinase. A protein that mediates the monocyte-suppressing activity of CNI-1493 has been purified and identified as fetuin, a negative acute phase protein that has previously been implicated as a carrier of biologically active factors. Fetuin now appears to occupy a critical role in the normal counter-regulation of monocytes, and CNI-1493 has proved extremely useful as a molecular tool to study the effects of proximal inhibition of macrophage activation in animal models of sepsis and injury. To date however, the effects of CNI-1493 in a clinically relevant animal model of trauma, injury, or hemorrhagic shock are unknown. Trauma and shock are known to induce a state of altered cytokine responsiveness in which the regulation of proinflammatory mediator synthesis is deranged. The objective of the studies outlined in this proposal is to determine whether CNI-1493 inhibits the synthesis of multiple macrophage- derived mediators in the altered cytokine milieu of post-traumatic sepsis. The experiments proposed in the Specific Aims will define the molecular basis for the binding and uptake of CNI-1493 and fetuin in human and murine monocytes, and characterize the effects of CNI-1493 and fetuin in a clinically relevant model of sepsis in animals previously subjected to surgery and hemorrhagic shock. This experimental design is expected to yield important new information concerning the endogenous mechanisms underlying the counter-regulation of proinflammatory cytokine production, and to identify new therapeutic strategies for the treatment of post-traumatic or post-operative sepsis based on deactivating the macrophage.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM057226-02
Application #
6180497
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
1999-09-30
Project End
2002-09-29
Budget Start
2000-09-30
Budget End
2001-09-29
Support Year
2
Fiscal Year
2000
Total Cost
$367,532
Indirect Cost
Name
North Shore University Hospital
Department
Type
DUNS #
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
Pavlov, Valentin A; Tracey, Kevin J (2017) Neural regulation of immunity: molecular mechanisms and clinical translation. Nat Neurosci 20:156-166
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:
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

Showing the most recent 10 out of 46 publications