Objective
To investigate the role of Nrf2 in the pathogenesis of hepatic ischemia-reperfusion (I/R) injury.
Summary Background Data
Hepatic I/R injury is a serious complication that leads to liver failure after liver surgery. NF-E2-related factor 2 (Nrf2) is a transcription factor that plays a critical role in protecting cells against oxidative stress. Therefore, it is suggested that Nrf2 activation protects the liver from I/R injury.
Methods
Wild-type (WT) and Nrf2-deficient mice were treated with 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2), or a vehicle. Subsequently, these mice were subjected to 60 min hepatic 70% ischemia followed by reperfusion. Liver and blood samples were collected to evaluate liver injury and mRNA expressions.
Results
After hepatic I/R, Nrf2-deficient livers exhibited enhanced tissue damage, impaired GSTm1, NQO1, and GCLc inductions, disturbed redox state, and aggravated TNF-α mRNA expression in comparison to WT livers. 15d-PGJ2 treatment protected the livers of WT mice from I/R injury via increased expressions of GSTm1, NQO1 and GCLc, maintained redox status, and decreased TNF-α induction. These effects induced by 15d-PGJ2 were not seen in the livers of Nrf2−/− mice and were not annulled by PPARγ antagonist in Nrf2+/+ mice, suggesting that the protective effect of 15d-PGJ2 is mediated by Nrf2-dependent antioxidant response.
Conclusions
Nrf2 plays a critical role in the mechanism of hepatic I/R injury and would be a new therapeutic target for preventing hepatic I/R injury during liver surgery.
The serum zinc, prealbumin, retinol-binding protein and carotene concentrations and the plasma fatty acid composition were determined to assess the nutritional condition of 24 patients with chronic pancreatitis compared with that of 20 healthy controls. The daily food intake and faecal fat excretion of the two groups were also measured. In the chronic pancreatitis group, the calorie and fat intakes were significantly lower than those of the controls. Serum levels of zinc, prealbumin and carotene were also significantly lower than those of the controls. Percentages of plasma linoleic and arachidonic acids were low, while percentages of palmitoleic acid, eicosapentaenoic acid and docosahexaenoic acid were high. Fish oil intake correlated negatively with plasma linoleic acid concentration (P < 0.05). The above results indicate that the relatively high intake of fish oil and the relatively low intake of dietary fat in Japanese patients with chronic pancreatitis with a mild degree of steatorrhoea results in an abnormally low plasma level of linoleic acid.
Infections by dermatophytes (dermatophytosis) naturally stimulate the immune system as in those by other microorganisms to induce various immunological phenomena. However, differing from other infections, the infecting organisms cannot become a direct target of antibody response or phagocytosis because they reside only in the barrier membrane of the body surface, i.e. in the stratum corneum.Thus, the immunity against dermatophytes is relative as compared with the absolute one noted in other infections such as measles and mumps. In dermatophytosis, a unique behavior of the epidermis as noted in contact dermatitis plays an important role in the defense against infection. Dermatitic changes induced by fungal products, particularly those due to contact sensitivity to a fungal antigen, trichophytin, enhance epidermopoiesis, which leads to increased turnover of the epidermis with their resultant elimination from the skin surface. Furthermore, the dermatophytes in the stratum corneum provoke transepidermal leukocyte chemotaxis by generating chemotactic C5a anaphylatoxin in exudating serum via alternative complement pathway activation in addition to a release of low molecular weight chemotactic factors. Such neutrophilic migration with the formation of subcorneal pustules also enhances epidermal proliferation as in psoriasis.
Background
The remnant liver after extended liver resection is susceptible to ischemic injury, resulting in the failure of liver regeneration and liver dysfunction. The present study is aimed to investigate the protective role of the liver epithelial cells (LEC), a liver progenitor cell, on hepatocytes with ischemia in vitro and in vivo.
Methods
LECs were isolated from rats and cultured under hypoxic conditions (2% O2). The cell viability and intracellular ATP levels were measured. The activation of hypoxia-inducible factor-1α (HIF-1α) was assessed by immunofluorescence. The expression of pyruvate dehydrogenase kinase-1 (PDK-1), stromal cell–derived factor-1 (SDF-1), and chemokine receptor 4 (CXCR4) were measured. Hepatocytes were treated with SDF-1 or LEC-conditioned medium under hypoxia, and cell viability was assessed. Finally, hemorrhagic shock was induced in rats with in vivo induction of endogenous LECs, and liver damage was assessed.
Results
In LECs, but not in hepatocytes, cellular viability and intracellular ATP levels were maintained, and nuclear translocation of HIF-1α and expression of pyruvate dehydrogenase kinase-1 mRNA were increased under hypoxic culture conditions. LECs express SDF-1, and CXCR4 expression was increased in hepatocytes under hypoxia. The survival of hepatocytes under hypoxic condition was significantly increased after treatment with SDF-1 or LEC-conditioned medium. The protective effect of conditioned medium was impaired by CXCR4 antagonists. In vivo induction of endogenous LECs suppressed elevation of serum AST and ALT levels after hemorrhage shock and ischemia-reperfusion.
Conclusion
LECs are resistant to hypoxia and have a protective role for hepatocytes against hypoxia. Our results suggest that induction of endogenous LECs protected the liver from lethal insults by paracrine signaling of SDF-1 and differentiation into parenchymal cells. (Surgery 2012;152:869-78.)
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