Disruption of P-selectin signaling modulates cell trafficking and results in improved outcomes after mouse warm intestinal ischemia and reperfusion injury.
BACKGROUND
This study analyzes the role of T lymphocytes and neutrophils (PMN) in intestinal ischemia and reperfusion injury (IRI) using either P-selectin blockade or elimination.


METHODS
Using a model of severe mouse warm intestinal IRI, the following groups were performed: group 1: wild type C57BL6 no treatment; group 2: wild type treated with r-PSGL1-Ig; group 3: C57BL6 genetically deficient in P-selectin. Survival was assessed at day 7; intestine was assayed for histopathology, apoptosis, myeloperoxidase (MPO), inflammatory cytokines, hemoxygenase-1 (HO-1), and CD3 lymphocytes. Standard statistical comparison was undertaken.


RESULTS
The survival was significantly (P < 0.01) improved in the treatment groups: group 1, 50%; group 2, 90%; group 3, 100%. Graded histopathology and crypt apoptosis were improved in groups 2 and 3. MPO and CD3 positive cells were significantly reduced in groups 2 and 3. A significant reduction in inflammatory/Th1-type cytokines was seen in groups 2 and 3 as compared to group 1. Conversely, a significant increase in Th2-type cytokines and HO-1 production was seen selectively in groups 2 and 3.


CONCLUSIONS
This study demonstrates the importance of P-selectin signaling in warm, murine intestinal IRI in that either the blockade of or the genetic deficiency in P-selectin confers a survival advantage and reduction in tissue injury/inflammation. The mechanism involves a reduction of PMN and CD3 T cell infiltration and an alteration in the cytokine microenvironment in favor of a Th2 profile. These data implicate T lymphocyte as an important regulatory cell in this inflammatory process.
Farmer
Douglas G
DG
Department of Surgery, Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-7054, USA. dgfarmer@mednet.ucla.edu
Anselmo
Dean
D
Da Shen
Xiu
X
Ke
Bibo
B
Carmody
Ian C
IC
Gao
Feng
F
Lassman
Charles
C
McDiarmid
Sue V
SV
Shaw
Grey
G
Busuttil
Ronald W
RW
Kupiec-Weglinski
Jerzy W
JW
D000818:Animals; D017209:Apoptosis; D017252:CD3 Complex / Q000378:metabolism; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology* / Q000601:surgery; D051379:Mice; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D021381:Protein Transport; D015427:Reperfusion Injury / Q000503:physiopathology*; D015398:Signal Transduction; D015996:Survival Rate; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D016896:Treatment Outcome; D052096:Warm Ischemia
D017252:CD3 Complex; D016207:Cytokines; D019007:P-Selectin; D009195:Peroxidase; D051547:Heme Oxygenase-1