CD62 blockade with P-Selectin glycoprotein ligand-immunoglobulin fusion protein reduces ischemia-reperfusion injury after rat intestinal transplantation.
BACKGROUND
Intestinal transplantation (ITx) is severely limited by ischemia-reperfusion (I/R) injury. This study investigates I/R injury and ameliorates its consequences by using a recombinant protein targeted against selectins (recombinant P-selectin glycoprotein ligand-immunoglobulin [rPSGL-Ig]).


METHODS
An isogeneic model of ITx was undertaken with control animals (no therapy) and treatment animals (rPSGL-Ig). Survival was assessed. Separate groups underwent an analysis examining tissue at multiple time points after I/R injury including histopathology; myeloperoxidase staining; immunostaining for CD3 and ED2; polymerase chain reaction analysis of interleukin (IL)-8/cytokine-inducible neutrophil chemoattractant, IL1beta, IL-6, interferon-gamma, IL-2, IL-4, and IL10; and western blots for hemoxygenase-1, BCL-2, and BCL-xl. Standard statistical analysis was undertaken.


RESULTS
Treatment with rPSGL-Ig resulted in significantly improved survival after ITx. Analysis demonstrated diminished injury on histopathology and reduced tissue infiltration of neutrophils and lymphocytes. Significant differences in the cytokine profile after ITx were seen between the two groups including the production of inflammatory cytokines at 24 hr and the Th1 and Th2 cytokines at 2 and 4 hr. Last, treatment resulted in increased production of hemoxygenase, BCL-2, and BCL-xl.


CONCLUSIONS
The results of this investigation of I/R injury after ITx revealed that rPSGL-Ig treatment led to marked improvement in outcome. The mechanism of action seems to involve the blockade of neutrophil and lymphocyte infiltration leading to a decreased inflammatory response possibly driven by Th2 cytokines. The results not only lend insight into the mechanisms behind I/R injury after ITx but also demonstrate a potential therapeutic modality to ameliorate its consequences.
Farmer
Douglas G
DG
Department of Surgery, Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. dgfarmer@mednet.ucla.edu
Shen
Xiu-Da
XD
Amersi
Farin
F
Anselmo
Dean
D
Ma
Jeffrey P
JP
Ke
Bibo
B
Gao
Feng
F
Dry
Sarah
S
Fernandez
Susan
S
Shaw
Gray D
GD
McDiarmid
Sue V
SV
Busuttil
Ronald W
RW
Kupiec-Weglinski
Jerzy
J
D000818:Animals; D017252:CD3 Complex / Q000032:analysis; D016207:Cytokines / Q000235:genetics; D007136:Immunoglobulins / Q000494:pharmacology*; D016209:Interleukin-8 / Q000235:genetics; D007422:Intestines / Q000098:blood supply* / Q000637:transplantation*; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D019007:P-Selectin / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000517:prevention & control*
D017252:CD3 Complex; D016207:Cytokines; D007136:Immunoglobulins; D016209:Interleukin-8; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D009195:Peroxidase