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(American Journal of Pathology. 2003;162:1229-1239.)
© 2003 American Society for Investigative Pathology

Fibronectin-{alpha}4ß1 Integrin-Mediated Blockade Protects Genetically Fat Zucker Rat Livers from Ischemia/Reperfusion Injury

Farin Amersi*, Xiu-Da Shen*, Carolina Moore*, Judy Melinek{dagger}, Ronald W. Busuttil*, Jerzy W. Kupiec-Weglinski* and Ana J. Coito*

From the Department of Surgery,* Division of Liver and Pancreas Transplantation, The Dumont-University of California at Los Angeles Transplant Center, Los Angeles; and the Department of Pathology and Laboratory Medicine,{dagger} University of California at Los Angeles School of Medicine, Los Angeles, California

We tested a hypothesis that interactions between fibronectin (FN), the major extracellular matrix component, and its integrin {alpha}4ß1 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}4ß1 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}4ß1 interaction protects against severe ischemia/reperfusion injury experienced otherwise by steatotic OLTs. These novel findings document the potential of targeting FN-{alpha}4ß1 in vivo interaction to increase the transplant donor pool through modulation of marginal steatotic livers.




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