Nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated induction of antioxidants has been implicated to have protective roles in ischemia-reperfusion (I/R) injury in many animal models. However, the in vivo effects of CDDO-imidazole (CDDO-Im) (1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole), a Nrf2 activator, in hepatic I/R injury is lacking and its exact molecular mechanisms are still not very clear. The goals of this study were to determine whether CDDO-Im can prevent liver injury induced by I/R in the mouse, and to elucidate the molecular target of drug action. Mice were randomly equally divided into two groups and administered intraperitoneally with either DMSO control or CDDO-Im (2 mg/kg) 3 h before subjected to 90-min hepatic 70% ischemia followed by reperfusion. Subsequently, the Liver and blood samples of these mice were collected to evaluate liver injury. CDDO-Im pretreatment markedly improve hepatic I/R injury by attenuating hepatic necrosis and apoptosis, reducing reactive oxygen species (ROS) levels and inflammatory responses, and ameliorating mitochondrial dysfunction. Mechanistically, by using Nrf2 Knockout mice and hemeoxygenase 1 (HO-1) inhibitor, we found that these CDDO-Im protection effects are attributed to enhanced autophagy, which is mediated by activating Nrf2/HO-1 pathway. By accelerating autophagy and clearance of damaged mitochondria, CDDO-Im reduced the mtDNA release and ROS overproduction, and in turn decreased damage-associated molecular patterns induced inflammatory responses and the following secondary liver injury. These results indicate that by enhancing autophagy, CDDO-Im-mediated activation of Nrf2/HO-1 signaling could be a novel therapeutic strategy to minimize the adverse effects of hepatic I/R injury.

Osteopontin (OPN), a multifunctional protein, is involved in numerous pathological conditions including inflammation, immunity, angiogenesis, fibrogenesis and carcinogenesis in various tissues. Extensive studies have elucidated the critical role of OPN in cell signaling such as regulation of cell proliferation, migration, inflammation, fibrosis and tumor progression. In the liver, OPN interacts with integrins, CD44, vimentin and MyD88 signaling, thereby induces infiltration, migration, invasion and metastasis of cells. OPN is highlighted as a chemoattractant for macrophages and neutrophils during injury in inflammatory liver diseases. OPN activates hepatic stellate cells (HSCs) to exert an enhancer in fibrogenesis. The role of OPN in hepatocellular carcinoma (HCC) has also generated significant interests, especially with regards to its role as a diagnostic and prognostic factor. Interestingly, OPN acts an opposing role in liver repair under different pathological conditions. This review summarizes the current understanding of OPN in liver diseases. Further understanding of the pathophysiological role of OPN in cellular interactions and molecular mechanisms associated with hepatic inflammation, fibrosis and cancer may contribute to the development of novel strategies for clinical diagnosis, monitoring and therapy of liver diseases.

Inappropriate inflammation responses contribute to mortality during sepsis. Through Toll-like receptors (TLRs), reactive oxygen species (ROS) produced by NADPH oxidase could modulate the inflammation responses. Parkinson disease (autosomal recessive, early onset) 7 (Park7) has a cytoprotective role by eliminating ROS. However, whether Park7 could modulate inflammation responses and mortality in sepsis is unclear. Here, we show that, compared with wild-type mice, Park7^−/− mice had significantly increased mortality and bacterial burdens in sepsis model along with markedly decreased systemic and local inflammation, and drastically impaired macrophage phagocytosis and bacterial killing abilities. Surprisingly, LPS and phorbol-12-myristate-13-acetate stimulation failed to induce ROS and proinflammatory cytokine production in Park7^−/− macrophages and Park7-deficient RAW264.7 cells. Through its C-terminus, Park7 binds to p47^phox, a subunit of the NADPH oxidase, to promote NADPH oxidase-dependent production of ROS. Restoration of Park7 expression rescues ROS production and improves survival in LPS-induced sepsis. Together, our study shows that Park7 has a protective role against sepsis by controlling macrophage activation, NADPH oxidase activation and inflammation responses.

The initial process in liver regeneration after partial hepatectomy involves the recruitment of immune cells and the release of cytokines. Osteopontin (OPN), a pro-inflammatory protein, plays critical roles in immune cell activation and migration. Although OPN has been implicated in the pathogenesis of many liver diseases, the role of OPN in liver regeneration remains obscure. In the present study, we found that serum and hepatic OPN protein levels were significantly elevated in wild-type (WT) mice after partial hepatectomy (PHx) and that bile ductal epithelia were the major cell source of hepatic OPN. Compared to WT mice, OPN knockout (KO) mice exhibited delayed liver regeneration after PHx. This delay in OPN^-/- mice was attributed to impaired hepatic infiltration of macrophages and neutrophils, decreased serum and hepatic IL-6 levels, and blunted activation of macrophages after PHx. Furthermore, we demonstrate that the attenuated activation of macrophages is at least partially due to decreased hepatic and portal vein LPS levels in OPN^-/- mice. In response to decreased IL-6 levels, the activation of signal transducer and transcription (Stat) 3 was reduced in hepatocytes of OPN^-/- mice compared to WT mice after PHx. Consequently, hepatic activation of the downstream direct targets of IL6/Stat3, such as c-fos, c-jun, and c-myc, was also suppressed post-PHx in OPN^-/- mice compared to WT mice. Collectively, these results support a unique role for OPN during the priming phase of liver regeneration, in which OPN enhances the recruitment of macrophages and neutrophils, and triggers hepatocyte proliferation through Kupffer cell-derived IL-6 release and the downstream activation of Stat3.