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Author Notes:

E-mail: nod@wustl.edu

Conceived and designed the experiments: NOD CMC JAD.

Performed the experiments: JAD YX WMD BPY EMB.

Analyzed the data: JAD CMC YX NOD.

Contributed reagents/materials/analysis tools: NOD CMC.

Wrote the paper: JAD CMC NOD.

The authors thank Dr. Richard Hotchkiss for helpful discussions.

The authors also express thanks to all members of the Coopersmith and Davidson labs for helpful advice and assistance.

This work reflects equal contributions from the Coopersmith and Davidson laboratories.

The authors have declared that no competing interests exist.

Subjects:

Research Funding:

This work was supported by funding from the National Institutes of Health (GM66202 supplement collaborative grant to CMC for work with NOD, GM072808, GM095442 CMC, GM082008 JAD, and HL38180, DK56260, P30 DK52574 to NOD and a Shock Society Early Career Investigator Fellowship to JAD).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • MULTIDISCIPLINARY SCIENCES
  • TRIGLYCERIDE TRANSFER PROTEIN
  • CRITICAL-CARE MEDICINE
  • GUT-LYMPH HYPOTHESIS
  • EPITHELIAL APOPTOSIS
  • IMPROVES SURVIVAL
  • SEPTIC SHOCK
  • ORGAN DYSFUNCTION
  • DEFICIENT MICE
  • HOST-DEFENSE
  • IN-VIVO

Intestine-Specific Mttp Deletion Decreases Mortality and Prevents Sepsis-Induced Intestinal Injury in a Murine Model of Pseudomonas aeruginosa Pneumonia

Tools:

Journal Title:

PLoS ONE

Volume:

Volume 7, Number 11

Publisher:

, Pages e49159-e49159

Type of Work:

Article | Final Publisher PDF

Abstract:

Background: The small intestine plays a crucial role in the pathophysiology of sepsis and has been referred to as the "motor" of the systemic inflammatory response. One proposed mechanism is that toxic gut-derived lipid factors, transported in mesenteric lymph, induce systemic injury and distant organ failure. However, the pathways involved are yet to be defined and the role of intestinal chylomicron assembly and secretion in transporting these lipid factors is unknown. Here we studied the outcome of sepsis in mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO), which exhibit a block in chylomicron assembly together with lipid malabsorption. Methodology/Principal Findings: Mttp-IKO mice and controls underwent intratracheal injection with either Pseudomona s aeruginosa or sterile saline. Mttp-IKO mice exhibited decreased seven-day mortality, with 0/20 (0%) dying compared to 5/17 (29%) control mice (p < 0.05). This survival advantage in Mttp-IKO mice, however, was not associated with improvements in pulmonary bacterial clearance or neutrophil infiltration. Rather, Mttp-IKO mice exhibited protection against sepsis-associated decreases in villus length and intestinal proliferation and were also protected against increased intestinal apoptosis, both central features in control septic mice. Serum IL-6 levels, a major predictor of mortality in human and mouse models of sepsis, were elevated 8-fold in septic control mice but remained unaltered in septic Mttp-IKO mice. Serum high density lipoprotein (HDL) levels were reduced in septic control mice but were increased in septic Mttp-IKO mice. The decreased levels of HDL were associated with decreased hepatic expression of apolipoprotein A1 in septic control mice. Conclusions/Significance: These studies suggest that strategies directed at blocking intestinal chylomicron secretion may attenuate the progression and improve the outcome of sepsis through effects mediated by metabolic and physiological adaptations in both intestinal and hepatic lipid flux.

Copyright information:

© 2012 Dominguez et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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