Cell-specific overactivation of nuclear erythroid 2 p45-related factor 2-mediated gene expression in myeloid cells decreases hepatic ischemia/reperfusion injury.

Abstract

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.

• Authors: Lung-Yi Lee, Calvin Harberg, Kristina A Matkowskyj, Shelly Cook, Drew Roenneburg, Sabine Werner, Delinda A Johnson, Jeffrey A Johnson, David P Foley
• Journal: Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society (Liver Transpl) Vol. 22 Issue 8 Pg. 1115-28 (08 2016) ISSN: 1527-6473 [Electronic] United States
• PMID: 27113842 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 American Association for the Study of Liver Diseases.

Chemical References

• Cytokines
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Alanine Transaminase
• Casp3 protein, mouse
• Caspase 3

Topics

• Alanine Transaminase (blood)
• Animals
• Antioxidant Response Elements
• Apoptosis
• Caspase 3 (metabolism)
• Cytokines (metabolism)
• Disease Models, Animal
• End Stage Liver Disease (surgery)
• Humans
• Immunohistochemistry
• Kupffer Cells (metabolism)
• Liver (cytology, pathology)
• Liver Transplantation (adverse effects)
• Mice
• Mice, Transgenic
• Monocytes (metabolism)
• NF-E2-Related Factor 2 (genetics, metabolism)
• Necrosis
• Neutrophils (metabolism)
• Oxidative Stress
• Reperfusion Injury (blood, etiology, metabolism)
• Signal Transduction
• Up-Regulation