肾上腺素对内毒素致大鼠炎症性肝损害的保护作用

Protective effects of epinephrine on liver injury caused by LPS in rats

目的探讨肾上腺素(Epi)对内毒素(脂多糖,LPS)致大鼠炎症性肝损害的保护作用及其作用机制。方法50只SD大鼠随机分为5组(每组各10只):对照组:静脉滴注生理盐水2.4mL·kg-1·h-1;LPS组:静脉注射LPS6mg·kg-1后,静脉滴注生理盐水2.4mL·kg-1·h-1;低、中和高剂量Epi组:静脉注射LPS6mg·kg-1后,分别静脉滴注Epi0.12、0.3和0.6μg·kg-1·min-1。在LPS注射前、注射后2和6h3个时点取血,检测血清ALT、AST、TNF-α、IL-1β和IL-10水平,并在6h时点观察肝脏的组织病理学改变。结果LPS组注射LPS后2、6h血清AST和ALT水平较对照组显著升高,同时血清TNF-α、IL-1β和IL-10水平亦较对照组显著升高(P<0.05)。病理检查结果示:LPS组肝窦扩张、充血,局灶性肝细胞坏死。高剂量Epi可显著降低血清AST和ALT水平,减轻肝脏病理损伤,并显著可降低TNF-α水平和升高IL-10水平(vsLPS组,P均<0.05),但对IL-1β水平无影响。中、低剂量Epi对LPS致炎症性肝损害无明显保护作用。结论Epi可通过抗炎作用减轻LPS诱导的炎症性肝损害。

Objective Epinephrine attenuates inflammation by inhibiting the production of pro-inflammatory cytokines, such as tumor necrosis factor（TNF）-α, interleukin （IL）-1β and by increasing the production of anti-inflammatory cytokine IL-10 in vivo and in vitro. In sepsis, activative inflammatory cells and excessive production of pro-inflammatory cytokines lead to tissue injury, multiple organ failure, and death. The liver is one of the major organ that can be damaged in sepsis and it may also trigger multiple organ dysfunction syndrome. Attenuation of hyper-inflammation may be of clinical benefit in the treatment of tissue injury associated with sepsis. So the aim of the study was to investigate the effects of epinephrine on sepsis-associated liver injury in rats. Methods Fifty SD rats were randomly divided into five groups （ n = 10） ： saline control group received intravenous 0. 9% saline 2. 4 mL·kg^-1·h^-1 ; LPS group received intravenous lipopolysaccharide （LPS） （ Escherichia coli serotype 0111 ： B 4 ） 6 mg ·kg^-1 ） ; small dose epinephrine treatment group received an intravenous infusion of epinephrine 0. 12μg·kg^-1·min^-1 after LPS intravenous injection; medium-dose epinephrine treatment group received an infusion of epinephrine 0. 3μg· kg^-1· min^-1 after the LPS intravenous injection; large-dose epinephrine treatment group received an infusion of epinephrine 0. 6 μg· kg^-1· min^-1 after LPS intravenous injection. Hepatic injury was evaluated by determining the levels of serum aspartate aminotransferase （ AST ） and alanine aminotransferase （ALT） and by liver pathological examination. Blood samples were taken 0, 2 and 6 h later and the levels of serum TNF-α, IL-1β, and IL-10 were detected by enzyme-linked immunoadsorbent assay （ELISA）. At the same time points, the levels of serum ALT and AST were also detected. The liver pathological changes were observed at 6 h. Results In LPS group, serum levels of ALT and AST were increased significantly compared with control group （ all P 〈 0.05 ） at 2 h and 6 h. Pathological examination showed that LPS could cause severe congestion of hepatic sinusoids and hepatocyte necrosis. Compared with LPS group, large-dose epinephrine reduced serum levels of ALT and AST （ P 〈 0. 05 ） and ameliorated the damage of liver tissue. In LPS group, serum levels of TNF-α, IL-1β,, IL-10 were all increased compared with control group （all P 〈0.05 ）. Compared with LPS group, serum levels of TNF-α were significantly reduced （ P 〈 0. 05 ）, whereas IL-10 was elevated （ P 〈 0.05 ） in large-dose epinephrine treatment group. Serum IL-1β levels were unaffected dose epinephrine could not reduce the levels of serum AST and by large-dose epinephrine treatment. Small-dose and medium- ALT and could not reduce the liver injury induced by LPS. Compared with LPS group, levels of serum TNF-α , IL-1β and IL-10 were also unaffected by small-dose and medium-dose epinephrine treatment（ all P 〉 0. 05） at any time points. Conclusions Epinephrine reduced the liver injury caused by LPS, down-regulated pro-inflammatory cytokines production and up-regulated anti-inflammatory cytokines production in rats. The anti- inflammatory effects may in part explain the protective effects of epinephrine on sepsis-associated liver injury. These results suggested that epinephrine may be useful in the treatment of liver injury associated with sepsis, shock, and other diseases associated with systemic inflammation.