title: Protective role of bortezomib in steatotic liver ischemia/reperfusion injury through abrogation of MMP activation and YKL-40 expression.
abstract: Steatotic liver grafts tolerate ischemia-reperfusion (I/R) injury poorly, contributing to poor survival following transplantation. However the molecular mechanisms leading to I/R injury still remain to be defined. We have previously reported that the protective effect of bortezomib towards inhibiting cold induced I/R injury in obese rat liver transplant model is through NF-κB down modulation. In this report using an orthotopic liver transplant (OLT) model in Zucker rats (from obese, leptin deficient donor, to lean recipient) we defined the mechanisms of steatotic liver injury, and characterized the role of bortezomib in inhibiting MMP activation and YKL-40, both of which are involved in extracellular matrix deposition and fibrosis, the key pathological features of liver allograft failure. Obese donor rats were treated with bortezomib (i.v., 0.1mg/kg immediately prior to liver procurement) to assess the role of MMP and YKL-40 in steatotic liver I/R injury. I/R injury in steatotic livers resulted in significant increases in expression of YKL-40 (9 fold), and activation of MMP-2 (15 fold)/MMP-9 (12 fold). Bortezomib treatment reduced the expression of YKL-40 and MMP to basal levels. Bortezomib also inhibited the pro-fibrotic (VEGF, HGF, bFGF, TGF-β) and pro-inflammatory (IL-1β, TNF-α and IFN-γ) cytokines significantly in comparison to untreated animals with I/R injury. These results demonstrate that I/R injury in steatotic livers following transplantation are associated with MMP activation and YKL-40 upregulation resulting in pro-fibrotic and pro-inflammatory cytokine release. Administration of the proteosomal inhibitor, bortezomib, effectively attenuated the I/R injury by inhibiting MMP and YKL-40 expression and therefore support the clinical utility of this drug in donor management for preventing I/R injury and its sequelae.
authors.affiliation: Department of Surgery, Washington University in St. Louis, School of Medicine, ST Louis, MO, United States; Department of Biological Sciences, Tennessee State University, Nashville, TN, United States. Electronic address: vtirivee@tnstate.edu.
authors.forename: Venkataswarup
authors.initials: V
authors.lastname: Tiriveedhi
authors.affiliation: Department of Surgery, Washington University in St. Louis, School of Medicine, ST Louis, MO, United States.
authors.forename: Gundumi A
authors.initials: GA
authors.lastname: Upadhya
authors.affiliation: Department of Surgery, Washington University in St. Louis, School of Medicine, ST Louis, MO, United States.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Busch
authors.affiliation: Department of Surgery, Washington University in St. Louis, School of Medicine, ST Louis, MO, United States.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Gunter
authors.affiliation: Department of Medicine, Washington University in St. Louis, School of Medicine, ST Louis, MO, United States.
authors.forename: Jeff N
authors.initials: JN
authors.lastname: Dines
authors.affiliation: Department of Medicine, Washington University in St. Louis, School of Medicine, ST Louis, MO, United States.
authors.forename: Bret L
authors.initials: BL
authors.lastname: Knolhoff
authors.affiliation: Department of Surgery, Washington University in St. Louis, School of Medicine, ST Louis, MO, United States.
authors.forename: Jianluo
authors.initials: J
authors.lastname: Jia
authors.affiliation: Department of Surgery, Washington University in St. Louis, School of Medicine, ST Louis, MO, United States.
authors.forename: Nayan J
authors.initials: NJ
authors.lastname: Sarma
authors.affiliation: Department of Surgery, Washington University in St. Louis, School of Medicine, ST Louis, MO, United States.
authors.forename: Sabarinathan
authors.initials: S
authors.lastname: Ramachandran
authors.affiliation: Department of Surgery, University of Mississippi Medical Center, Jackson, MS, United States.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Anderson
authors.affiliation: Department of Surgery, Washington University in St. Louis, School of Medicine, ST Louis, MO, United States; Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, ST Louis, MO, United States.
authors.forename: Thallachallour
authors.initials: T
authors.lastname: Mohanakumar
authors.affiliation: Department of Surgery, Washington University in St. Louis, School of Medicine, ST Louis, MO, United States. Electronic address: chapmanwi@wudosis.wustl.edu.
authors.forename: William C
authors.initials: WC
authors.lastname: Chapman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D000071451:Chitinase-3-Like Protein 1; D004789:Enzyme Activation / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis*; D005234:Fatty Liver / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006023:Glycoproteins / Q000096:biosynthesis*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; C507621:CHI3L1 protein, rat; D000071451:Chitinase-3-Like Protein 1; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D011719:Pyrazines; D000069286:Bortezomib; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
keywords: Bortezomib; I/R injury; Liver transplantation; Matrix metalloproteinases; YKL-40