Therapeutic efficacy of CXCR3 blockade in an experimental model of severe sepsis

Daniela S. Herzig, Yin Guo, Geping Fang, Tracy Toliver-Kinsky, Edward R. Sherwood

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Introduction: In our previous studies we demonstrated that CXC chemokine receptor 3 (CXCR3) participates in the regulation of lymphocyte trafficking during cecal ligation and puncture (CLP)-induced sepsis. In this study, we evaluated the effects of treatment with anti-CXCR3 immunoglobulin (IgG) and antibiotics on outcome during septic shock caused by CLP.Methods: C57BL/6J mice were treated with neutralizing IgG against CXCR3 plus Primaxin either 24 hours prior to, 2 hours after or 6 hours after CLP. Control mice received nonspecific IgG plus Primaxin in the same regimen. Survival, core body temperature, bacterial clearance and systemic cytokine production were evaluated.Results: Our results show that treatment with anti-CXCR3 IgG plus Primaxin significantly improved survival when administered 24 hours prior to CLP (50% vs. 10%), 2 hours after CLP (55% vs. 10%) or 6 hours after CLP (55% vs. 25%) compared with mice receiving nonspecific IgG plus Primaxin. Treatment with anti-CXCR3 plus Primaxin 24 hours prior to CLP attenuated hypothermia and IL-6 and macrophage inflammatory protein 2 (MIP-2) production but did not alter bacterial clearance. Treatment with anti-CXCR3 IgG and Primaxin 2 hours after CLP did not improve bacterial clearance and systemic cytokine production compared with mice treated with IgG and Primaxin, whereas 6 hours after CLP the bacterial clearance and IL-6 and MIP-2 concentrations, both in plasma and peritoneal lavage fluid, were significantly improved in mice receiving anti-CXCR3 IgG and Primaxin compared with mice that only received nonspecific IgG and Primaxin.Conclusion: The results from this study indicate that neutralization of CXCR3 prior to, 2 hours after or 6 hours after the initiation of CLP-induced septic shock improves survival and attenuates CLP-induced inflammation and physiologic dysfunction.

Original languageEnglish (US)
Article numberR168
JournalCritical Care
Volume16
Issue number5
DOIs
StatePublished - Sep 19 2012

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CXCR3 Receptors
Punctures
Ligation
Sepsis
Theoretical Models
Immunoglobulin G
Therapeutics
Chemokine CXCL2
Septic Shock
Interleukin-6
Cytokines
Peritoneal Lavage
imipenem drug combination cilastatin
Ascitic Fluid
Hypothermia
Body Temperature
Inbred C57BL Mouse

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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Therapeutic efficacy of CXCR3 blockade in an experimental model of severe sepsis. / Herzig, Daniela S.; Guo, Yin; Fang, Geping; Toliver-Kinsky, Tracy; Sherwood, Edward R.

In: Critical Care, Vol. 16, No. 5, R168, 19.09.2012.

Research output: Contribution to journalArticle

Herzig, Daniela S. ; Guo, Yin ; Fang, Geping ; Toliver-Kinsky, Tracy ; Sherwood, Edward R. / Therapeutic efficacy of CXCR3 blockade in an experimental model of severe sepsis. In: Critical Care. 2012 ; Vol. 16, No. 5.
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AB - Introduction: In our previous studies we demonstrated that CXC chemokine receptor 3 (CXCR3) participates in the regulation of lymphocyte trafficking during cecal ligation and puncture (CLP)-induced sepsis. In this study, we evaluated the effects of treatment with anti-CXCR3 immunoglobulin (IgG) and antibiotics on outcome during septic shock caused by CLP.Methods: C57BL/6J mice were treated with neutralizing IgG against CXCR3 plus Primaxin either 24 hours prior to, 2 hours after or 6 hours after CLP. Control mice received nonspecific IgG plus Primaxin in the same regimen. Survival, core body temperature, bacterial clearance and systemic cytokine production were evaluated.Results: Our results show that treatment with anti-CXCR3 IgG plus Primaxin significantly improved survival when administered 24 hours prior to CLP (50% vs. 10%), 2 hours after CLP (55% vs. 10%) or 6 hours after CLP (55% vs. 25%) compared with mice receiving nonspecific IgG plus Primaxin. Treatment with anti-CXCR3 plus Primaxin 24 hours prior to CLP attenuated hypothermia and IL-6 and macrophage inflammatory protein 2 (MIP-2) production but did not alter bacterial clearance. Treatment with anti-CXCR3 IgG and Primaxin 2 hours after CLP did not improve bacterial clearance and systemic cytokine production compared with mice treated with IgG and Primaxin, whereas 6 hours after CLP the bacterial clearance and IL-6 and MIP-2 concentrations, both in plasma and peritoneal lavage fluid, were significantly improved in mice receiving anti-CXCR3 IgG and Primaxin compared with mice that only received nonspecific IgG and Primaxin.Conclusion: The results from this study indicate that neutralization of CXCR3 prior to, 2 hours after or 6 hours after the initiation of CLP-induced septic shock improves survival and attenuates CLP-induced inflammation and physiologic dysfunction.

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