Cell-specific overactivation of nuclear erythroid 2 p45-related factor 2-mediated gene expression in myeloid cells decreases hepatic ischemia/reperfusion injury.
Hepatic ischemia/reperfusion injury (IRI) is an unavoidable consequence of liver transplantation that can lead to postoperative hepatic dysfunction. Myeloid cells that include Kupffer cells, monocytes, and neutrophils contribute to the inflammatory response and cellular injury observed during hepatic IRI. We hypothesize that overactivation of the nuclear erythroid 2 p45-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway in myeloid cells leads to decreased cellular damage after hepatic IRI. We constructed transgenic mice with constitutively active nuclear erythroid 2 p45-related factor 2 (caNrf2) that over activates the Nrf2-ARE pathway in myeloid cells (lysozyme M cre recombinase [LysMcre]+/caNrf2+, n = 9), and their littermate controls lacking transgene expression (LysMcre+/caNrf2-, n = 11). The mice underwent either sham or partial hepatic ischemia surgery, with 60 minutes of ischemia followed by 6 hours of reperfusion. After IRI, LysMcre+/caNrf2+ mice demonstrated significantly decreased serum alanine aminotransferase and decreased areas of necrosis. Immunohistochemistry and immunoblot of caspase 3 showed a significantly decreased cleaved to full-length caspase 3 ratio in LysMcre+/caNrf2+ animals. Lymphocyte antigen 6 complex locus G and CD68 staining demonstrated reduced inflammatory cell infiltration. LysMcre+/caNrf2+ animals also had significantly decreased gene expression of proinflammatory cytokines, including interleukin (IL) 1β, IL6, tumor necrosis factor α, chemokine (C-C motif) ligand 2, and chemokine (C-X-C motif) ligand 10, and significantly decreased levels of 8-isoprostanes. In our model, Nrf2 overactivation in myeloid cells leads to decreased hepatocellular damage, necrosis, apoptosis, inflammation, and oxidative stress. Pharmacologic targeting of the Nrf2-ARE pathway in myeloid cells may be a novel strategy to mitigate hepatic IRI. Liver Transplantation 22 1115-1128 2016 AASLD.
Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Lung-Yi
LY
Lee
Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Calvin
C
Harberg
Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI.|Veterans Administration Pathology Services, William S. Middleton Memorial Hospital, Madison, WI.
Kristina A
KA
Matkowskyj
Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Shelly
S
Cook
Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Drew
D
Roenneburg
Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, Zurich, Switzerland.
Sabine
S
Werner
Division of Pharmaceutical Sciences, University of Wisconsin, Madison, WI.|Molecular and Environmental Toxicological Center, University of Wisconsin, Madison, WI.
Delinda A
DA
Johnson
Division of Pharmaceutical Sciences, University of Wisconsin, Madison, WI.|Molecular and Environmental Toxicological Center, University of Wisconsin, Madison, WI.|Center for Neuroscience, University of Wisconsin, Madison, WI.|Waisman Center, University of Wisconsin, Madison, WI.
Jeffrey A
JA
Johnson
Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI.|Veterans Administration Surgical Services, William S. Middleton Memorial Hospital, Madison, WI.
David P
DP
Foley
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D061745:Antioxidant Response Elements; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D058625:End Stage Liver Disease / Q000601:surgery*; D006801:Humans; D007150:Immunohistochemistry; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000473:pathology*; D016031:Liver Transplantation / Q000009:adverse effects*; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis; D009504:Neutrophils / Q000378:metabolism; D018384:Oxidative Stress; D015427:Reperfusion Injury / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
D016207:Cytokines; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000410:Alanine Transaminase; C505409:Casp3 protein, mouse; D053148:Caspase 3