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+/caN-rf2+ 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.

p62/SQSTM1—Dr. Jekyll and Mr. Hyde that prevents oxidative stress but promotes liver cancer

“…Conversely, Nrf2 −/− mice are more sensitive to APAP‐induced hepatotoxicity than wild‐type mice , whereas liver‐specific Keap1 −/− mice, in which NRF2 is constitutively activated, are more resistant to APAP than control mice . Constitutive NRF2 activation in myeloid cells also results in decreased liver damage, necrosis, apoptosis, inflammation, and oxidative stress in a mouse model of liver ischemia and reperfusion injury . However, constitutive liver‐specific NRF2 activation does not protect from carbon tetrachloride (CCl 4 )‐induced liver injury and fibrosis .…”

Pre‐conditions for eliminating mitochondrial dysfunction and maintaining liver function after hepatic ischaemia reperfusion

“…Prdx6‐knockout mice exhibit more mitochondrial dysfunction and hepatocellular injury, and the generation of mitochondrial hydrogen peroxide is increased . Furthermore, overexpression of Nrf2 decreases the release of inflammatory cytokines and 8‐isoprostanes, thus protecting the liver against hepatic IR injury . A plasmid with a receptor activator for NF‐κB‐Fc has been found to exert prominent effects, protecting against hepatocellular apoptosis in hepatic IR mice by inhibiting NF‐κB nuclear translocation, JNK phosphorylation and HIF‐1α expression .…”

Intraperitoneal administration of apigenin in liver ischemia/reperfusion injury protective effects

“…in 2016, the Kupffer cell activation contributes to the inflammatory response, and inhibition of this activation can lead to less hepatocellular damage during I/R injury. [33]…”