The effect of losartan on the inflammatory damage through HMGB1 in the hepatocytes stimulated by heat stress / 解放军医学杂志

ABSTRACT

Objective To explore the function of losartan on heat-stress induced high-mobility group protein B1 (HMGB1) mediated inflammatory damage in the hepatocytes. Methods Rats were randomized into three groups sham group (without heat stress), heatstroke group (heatstroke induction followed by i.p. injection of normal saline) and heatstroke+losartan group (heatstroke induction followed by i.p. injection of 50 mg/kg losartan). The serum and liver tissue were harvested nine hours after heatstroke to invest the serum alanine aminotransferase (ALT) levels, liver myeloperoxidase (MPO) levels, liver pathological morphology, serum HMGB1 levels as well as the expression of interleukin(IL)-1β and IL-18 in the liver. In vitro, the HBL3A hepatocyte cell lines were divided into the sham group (without heat stress), heat stress group and heat stress +losartan group (10 μmol/L losartan added into the supernatant after heat stress). Nine hours after heat stress, the cell viability and the levels of supernatant lactate dehydrogenase, supernatant HMGB, cytoplasm and total HMGB1 were all examined. Besides, the level of activated caspase-1 in hepatocytes, supernatant IL-1β and IL-18, as well as the cellular level of reactive oxygen species (ROS), were detected. The effects of recombinant HMGB1 with concentration gradients and 0.2 mmol/L hydrogen peroxide on the levels of IL-1β, IL-18 and HMGB1 in the heat stress hepatocytes treated by losartan were observed. Results In vivo, liver damage occurred in the rats of the heatstroke group. Compared with the heatstroke group, the levels of serum ALT, liver MPO, serum HMGB1, liver tissue IL-1β and IL-18 decreased in the heatstroke+losartan group (P<0.05). In vitro, hepatocytes in the heat stress group were apparently damaged. Compared with the heat stress, the levels of cytoplasmic HMGB1, supernatant HMGB1, IL-1β and IL-18 decreased in the heat stress+losartan group, and the cell survival rate increased (P<0.05). In addition, the HMGB1 inhibitor also reduced the levels of IL-1β and IL-18 in heat stress group hepatocytes. And the supplementation with HMGB1 increased the levels of IL-1β and IL-18 in heat stress hepatocytes treated by losartan (P<0.05). Losartan reduced the level of reactive oxygen species in heat stress hepatocytes, and the supplementation with hydrogen peroxide increased the level of HMGB1 in heat stress hepatocytes treated by losartan (P<0.05). Conclusion Losartan decreased the heat-stress induced HMGB1 mediated inflammatory damage in the hepatocytes.