Induction of endotoxin tolerance enhances bacterial clearance and survival in murine polymicrobial sepsis

Derek S. Wheeler, Patrick M. Lahni, Alvin G. Denenberg, Sue E. Poynter, Hector R. Wong, James A. Cook, Basilia Zingarelli

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

Abstract

The fundamental mechanisms that underlie endotoxin tolerance remain to be elucidated, and the clinical significance of endotoxin tolerance in the context of active systemic infection remains in question. We hypothesized that the endotoxin tolerance phenotype would result in decreased inflammation at the expense of altered bacterial clearance and, thus, higher mortality in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Endotoxin tolerance was induced in C57BI/6 mice with 5 mg/kg LPS or vehicle 18 h before subsequent CLP. Lung tissue, peritoneal fluid, and blood were collected at 1, 3, 6, and 18 h after surgery for subsequent analysis. Peritoneal macrophages were isolated for ex vivo phagocytosis assay. In separate experiments, mice were allowed to recover, and survival was monitored for 7 days. Endotoxin tolerance attenuated plasma TNF-α and IL-6 at 6 h after CLP. Peritoneal fluid cytokines were significantly attenuated as well. Endotoxin tolerance significantly improved bacterial clearance in both blood and peritoneal fluid after CLP. Similarly, ex vivo phagocytosis by primary peritoneal macrophages and RAW264.7 murine peritoneal macrophages was significantly improved after induction of the endotoxin tolerance phenotype. Contrary to our original hypothesis, we conclude that endotoxin tolerance significantly attenuates the host inflammatory response, augments bacterial clearance, and improves survival in this murine model of polymicrobial sepsis.

Original languageEnglish (US)
Pages (from-to)267-273
Number of pages7
JournalShock
Volume30
Issue number3
DOIs
StatePublished - Sep 2008
Externally publishedYes

Keywords

  • Inflammation
  • LPS
  • Phagocytosis
  • Rodent
  • Tolerance

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

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