During the current funding period, we made significant progress defining the role of CXC chemokine receptor 3 (CXCR3) in the pathogenesis of septic shock. Our results show that CXCR3 is an important regulator of natural killer cell trafficking during septic shock caused by cecal ligation and puncture (CLP). Furthermore, CXCR3 deficiency or blockade causes significant attenuation of sepsis-induced physiologic dysfunction, systemic cytokine production and survival. Deficiency or blockade of the CXCR3 ligand CXCL10 also conferred protection from CLP-induced septic shock. Survival benefit was achievable when anti-CXCR3 IgG or anti- CXCL10 IgG was administered with fluids and antibiotics at 6 hours after CLP. Therefore, CXCR3 blockade was effective when initiated after the onset of sepsis and may represent a viable addition to a multi-modal approach for the treatment of septic shock. Yet, several questions remain regarding the efficacy of CXCR3 blockade in clinically relevant models of sepsis and the mechanisms by which the CXCR3 axis is activated during sepsis. The goals of this research project are two-fold: 1) To evaluate clinically relevant approaches for CXCR3 blockade with the goal of bringing this approach closer to application in the clinical setting and 2) To define the mechanisms by which CXCR3 activation facilitates the pathogenesis of septic shock and determine the cellular and molecular mechanisms by which the CXCR3 axis is activated during sepsis.
Specific Aim 1 : To define the efficacy of CXCR3 blockade in clinically relevant models of sepsis. In this aim, we will evaluate the efficacy of CXCR3 blockade when initiated after the onset of severe sepsis as indicated by the development of hypoperfusion and organ injury. The CLP model will be utilized as well as our well-developed models of Pseudomonas aeruginosa and Staphylococcus aureus burn wound sepsis. The efficacy of the small molecular weight CXCR3 inhibitor AMG487 will be determined in addition to immunoglobulin-based strategies.
Specific Aim 2 : To determine the role of the CXCR3 axis in the host response to infection. Some recent studies indicate that CXCL10 plays a role in facilitating effective bacterial clearance mechanisms in less severe models of systemic infection. Studies proposed in this aim will determine whether CXCR3 axis blockade will impair the host response to local infection and whether blockade of the CXCR3 axis during the acute phase of severe sepsis will predispose the host to secondary infections.
Specific Aim 3 : To define the mechanisms by which the CXCR3 axis is activated during septic shock and define the cell populations responsible for CXCR3- mediated pathobiology. These studies will define the mechanisms that regulate CXCL10 production in vivo. Emphasis will be placed on evaluating the importance of interferon signaling pathways. Further studies are proposed to determine the functional importance of CXCR3-mediated lymphocyte trafficking during severe sepsis and whether CXCR3 serves as an activating factor for non-migratory lymphocyte populations.

Public Health Relevance

Sepsis is a major cause of death in critically ill patients. The information gained from this project will advance our ability to treat severe sepsis and fill important gaps in knowledge by advancing our understanding of how the CXCR3 axis contributes to sepsis-induced pathobiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM066885-11
Application #
8578744
Study Section
Special Emphasis Panel (ZRG1-SBIB-X (02))
Program Officer
Dunsmore, Sarah
Project Start
2003-07-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
11
Fiscal Year
2013
Total Cost
$386,100
Indirect Cost
$138,600
Name
Vanderbilt University Medical Center
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Herzig, Daniela S; Luan, Liming; Bohannon, Julia K et al. (2014) The role of CXCL10 in the pathogenesis of experimental septic shock. Crit Care 18:R113
Bohannon, Julia K; Hernandez, Antonio; Enkhbaatar, Perenlei et al. (2013) The immunobiology of toll-like receptor 4 agonists: from endotoxin tolerance to immunoadjuvants. Shock 40:451-62
Herzig, Daniela S; Driver, Brandon R; Fang, Geping et al. (2012) Regulation of lymphocyte trafficking by CXC chemokine receptor 3 during septic shock. Am J Respir Crit Care Med 185:291-300
Romero, Christopher D; Varma, Tushar K; Hobbs, Jason B et al. (2011) The Toll-like receptor 4 agonist monophosphoryl lipid a augments innate host resistance to systemic bacterial infection. Infect Immun 79:3576-87
Romero, Christopher R; Herzig, Daniela S; Etogo, Anthony et al. (2010) The role of interferon-? in the pathogenesis of acute intra-abdominal sepsis. J Leukoc Biol 88:725-35
Etogo, Anthony O; Nunez, Jesus; Lin, Cheng Y et al. (2008) NK but not CD1-restricted NKT cells facilitate systemic inflammation during polymicrobial intra-abdominal sepsis. J Immunol 180:6334-45
Enoh, Victor T; Lin, Scott H; Etogo, Anthony et al. (2008) CD4+ T-cell depletion is not associated with alterations in survival, bacterial clearance, and inflammation after cecal ligation and puncture. Shock 29:56-64
Enoh, Victor T; Lin, Scott H; Lin, Cheng Y et al. (2007) Mice depleted of alphabeta but not gammadelta T cells are resistant to mortality caused by cecal ligation and puncture. Shock 27:507-19
Enoh, Victor T; Lin, Cheng Y; Varma, Tushar K et al. (2006) Differential effect of imipenem treatment on injury caused by cecal ligation and puncture in wild-type and NK cell-deficient beta(2)-microgloblin knockout mice. Am J Physiol Gastrointest Liver Physiol 290:G277-84
Enoh, Victor T; Fairchild, Chad D; Lin, Cheng Y et al. (2006) Differential effect of imipenem treatment on wild-type and NK cell-deficient CD8 knockout mice during acute intra-abdominal injury. Am J Physiol Regul Integr Comp Physiol 290:R685-93

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