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2016 ; 46
(1
): 52-9
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Mechanisms of Intestinal Barrier Dysfunction in Sepsis
#MMPMID27299587
Yoseph BP
; Klingensmith NJ
; Liang Z
; Breed ER
; Burd EM
; Mittal R
; Dominguez JA
; Petrie B
; Ford ML
; Coopersmith CM
Shock
2016[Jul]; 46
(1
): 52-9
PMID27299587
show ga
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.
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