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Author Notes:

Address correspondence to: Craig M Coopersmith, 101 Woodruff Circle, Suite WMB 5105, Atlanta, GA 30322, Phone: (404) 727-4273, Fax: (404) 727-3660, cmcoop3@emory.edu

Conflicts of Interest: Craig Coopersmith was the President of the Society of Critical Care Medicine when this work was submitted.

Subjects:

Research Funding:

This work was supported by funding from the National Institutes of Health (GM072808, GM095442, GM104323, GM109779, GM113228).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Critical Care Medicine
  • Hematology
  • Surgery
  • Peripheral Vascular Disease
  • General & Internal Medicine
  • Cardiovascular System & Cardiology
  • Barrier
  • cecal ligation and puncture
  • claudin
  • gut
  • intestine
  • JAM-A
  • occludin
  • permeability
  • pneumonia
  • sepsis
  • ZO
  • PSEUDOMONAS-AERUGINOSA PNEUMONIA
  • DIFFERENTIAL EXPRESSION
  • POLYMICROBIAL SEPSIS
  • TIGHT JUNCTIONS
  • MUCOSAL BARRIER
  • IN-VIVO
  • MORTALITY
  • GUT
  • LOCALIZATION
  • DISRUPTION

Mechanisms of Intestinal Barrier Dysfunction in Sepsis

Tools:

Journal Title:

Shock

Volume:

Volume 46, Number 1

Publisher:

, Pages 52-59

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Intestinal barrier dysfunction is thought to contribute to the development of multiple organ dysfunction syndrome in sepsis. Although there are similarities in clinical course following sepsis, there are significant differences in the host response depending on the initiating organism and time course of the disease, and pathways of gut injury vary widely in different preclinical models of sepsis. The purpose of this study was to determine whether the timecourse and mechanisms of intestinal barrier dysfunction are similar in disparate mouse models of sepsis with similar mortalities. FVB/N mice were randomized to receive cecal ligation and puncture (CLP) or sham laparotomy, and permeability was measured to fluoresceinisothiocyanate conjugated-dextran (FD-4) six to 48 h later. Intestinal permeability was elevated following CLP at all timepoints measured, peaking at 6 to 12 h. Tight junction proteins claudin 1, 2, 3, 4, 5, 7, 8, 13, and 15, Junctional Adhesion Molecule-A (JAM-A), occludin, and ZO-1 were than assayed by Western blot, real-time polymerase chain reaction, and immunohistochemistry 12 h after CLP to determine potential mechanisms underlying increases in intestinal permeability. Claudin 2 and JAM-A were increased by sepsis, whereas claudin-5 and occludin were decreased by sepsis. All other tight junction proteins were unchanged. A further timecourse experiment demonstrated that alterations in claudin-2 and occludin were detectable as early as 1 h after the onset of sepsis. Similar experiments were then performed in a different group of mice subjected to Pseudomonas aeruginosa pneumonia. Mice with pneumonia had an increase in intestinal permeability similar in timecourse and magnitude to that seen in CLP. Similar changes in tight junction proteins were seen in both models of sepsis although mice subjected to pneumonia also had a marked decrease in ZO-1 not seen in CLP. These results indicate that two disparate, clinically relevant models of sepsis induce a significant increase in intestinal permeability mediated through a common pathway involving alterations in claudin 2, claudin 5, JAM-A, and occludin although model-specific differences in ZO-1 were also identified.

Copyright information:

© 2016 by the Shock Society.

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