Fibronectin-alpha 4 beta 1 integrin-mediated blockade protects genetically fat Zucker rat livers from ischemia/reperfusion injury.
We tested a hypothesis that interactions between fibronectin (FN), the major extracellular matrix component, and its integrin alpha 4 beta 1 receptor is important in the development of ischemia/reperfusion injury of steatotic liver transplants. We examined the effect of connecting segment-1 (CS1) peptide-facilitated blockade of FN-alpha 4 beta 1 interaction in a well-established steatotic rat liver model of ex vivo cold ischemia followed by iso-transplantation. In this model, CS1 peptides were administered through the portal vein of steatotic Zucker rat livers before and after cold ischemic storage. Lean Zucker recipients of fatty liver transplants received an additional 3-day course of CS1 peptides after transplant. CS1 peptide therapy significantly inhibited the recruitment of T lymphocytes, neutrophil activation/infiltration, and repressed the expression of proinflammatory tumor necrosis factor-alpha and interferon-gamma. Moreover, it resulted in selective inhibition of inducible nitric oxide synthase expression, peroxynitrite formation, and hepatic necrosis. Importantly, CS1 peptide therapy improved function/histological preservation of steatotic liver grafts, and extended their 14-day survival in lean recipients from 40% in untreated to 100% in CS1-treated OLTs. Thus, CS1 peptide-mediated blockade of FN-alpha 4 beta 1 interaction protects against severe ischemia/reperfusion injury experienced otherwise by steatotic OLTs. These novel findings document the potential of targeting FN-alpha 4 beta 1 in vivo interaction to increase the transplant donor pool through modulation of marginal steatotic livers.
Amersi
Farin
F
Department of Surgery, Division of Liver and Pancreas Transplantation, The Dumont-University of California at Los Angeles Transplant Center, Los Angeles 90095, USA.
Shen
Xiu-Da
XD
Moore
Carolina
C
Melinek
Judy
J
Busuttil
Ronald W
RW
Kupiec-Weglinski
Jerzy W
JW
Coito
Ana J
AJ
D000818:Animals; D007150:Immunohistochemistry; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008102:Liver Circulation / Q000502:physiology*; D016031:Liver Transplantation / Q000473:pathology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D015427:Reperfusion Injury / Q000473:pathology* / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D039041:Integrin alpha4beta1; D010446:Peptide Fragments; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat