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. CONCLUSION: 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.
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. CONCLUSION: 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.
Authors: Sydney X Lu; Amanda M Holland; Il-Kang Na; Theis H Terwey; Onder Alpdogan; Jhoanne L Bautista; Odette M Smith; David Suh; Christopher King; Adam Kochman; Vanessa M Hubbard; Uttam K Rao; Nury Yim; Chen Liu; Alvaro C Laga; George Murphy; Robert R Jenq; Johannes L Zakrzewski; Olaf Penack; Lindsay Dykstra; Kevin Bampoe; Lia Perez; Bruce Furie; Barbara Furie; Marcel R M van den Brink Journal: J Immunol Date: 2010-07-09 Impact factor: 5.422
Authors: N M Valenzuela; L Hong; X-Da Shen; F Gao; S H Young; E Rozengurt; J W Kupiec-Weglinski; M C Fishbein; E F Reed Journal: Am J Transplant Date: 2012-12-27 Impact factor: 8.086
Authors: Douglas G Farmer; Bibo Ke; Xiu-Da Shen; Fady M Kaldas; Feng Gao; Melissa J Watson; Ronald W Busuttil; Jerzy W Kupiec-Weglinski Journal: Transplantation Date: 2011-04-15 Impact factor: 4.939
Authors: Anjuli R Kumar; Xiaoxiao Li; James F Leblanc; Douglas G Farmer; David Elashoff; Jonathan Braun; David Ziring Journal: Transplantation Date: 2011-07-15 Impact factor: 4.939
Authors: Davide Scozzi; Mohsen Ibrahim; Cecilia Menna; Alexander S Krupnick; Daniel Kreisel; Andrew E Gelman Journal: Am J Transplant Date: 2016-07-25 Impact factor: 8.086