Glavind Emilie, Vilstrup Hendrik, Grønbaek Henning, Hamilton-Dutoit Stephen, Magnusson Nils Erik, Thomsen Karen Louise
Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark.
Alcohol Clin Exp Res. 2017 Mar;41(3):562-570. doi: 10.1111/acer.13328. Epub 2017 Feb 3.
Long-term excessive alcohol intake predisposes to infectious diseases. The hepatic acute-phase response is a component of the innate immune system and is part of the first line of defense against invading pathogens, which may be compromised by alcohol. We aimed to investigate whether an induced acute-phase response is impaired in long-term ethanol (EtOH)-fed rats.
For 6 weeks, rats were either fed a Lieber-DeCarli EtOH-containing (36% as calories) liquid diet ad libitum or calorically pair-fed. Then, the rats were injected intraperitoneally with a low dose of lipopolysaccharide (LPS) (0.5 mg/kg) to induce an acute-phase response. Two hours after LPS, we measured the plasma concentrations of an array of inflammatory cytokines. Twenty-four hours after LPS, we measured the hepatic mRNA expression and serum concentrations of prominent rat acute-phase proteins.
EtOH-fed rats showed either no liver histopathological changes or varying degrees of steatosis. EtOH feeding decreased the spontaneous liver mRNA expression of the prevailing acute-phase protein alpha-2-macroglobulin (α2M) by 30% (p < 0.01). LPS immediately increased plasma tumor necrosis factor-alpha and interleukin-6 more than 100-fold in both feeding groups (p < 0.001, all) and approximately twice as much in the EtOH-fed rats (p < 0.05 and p = 0.08, respectively). LPS also induced a variable but marked amplification of (α2M), haptoglobin, alpha-1-acid glycoprotein, and lipocalin-2 liver mRNA expression levels and serum concentrations in both feeding groups (p ≤ 0.01 to 0.001). However, the LPS-induced increases in serum (α2M) and haptoglobin were less pronounced in the EtOH-fed rats, averaging approximately 60% of the concentrations in the pair-fed rats (p < 0.01 and p < 0.001, respectively).
Long-term EtOH exposure in rats reduces the spontaneous hepatic mRNA expression of (α2M) and markedly impairs the hepatic acute-phase response to endotoxin, despite higher pro-inflammatory cytokine release. The same phenomenon may contribute to the increased susceptibility to infections observed in humans with long-term excessive alcohol intake.
长期过量饮酒易引发感染性疾病。肝脏急性期反应是固有免疫系统的一个组成部分，是抵御入侵病原体的第一道防线的一部分，而这可能会因酒精而受到损害。我们旨在研究长期喂食乙醇（EtOH）的大鼠中诱导的急性期反应是否受损。
大鼠随意喂食含Lieber-DeCarli乙醇（占热量的36%）的液体饮食或按热量配对喂食6周。然后，给大鼠腹腔注射低剂量脂多糖（LPS）（0.5mg/kg）以诱导急性期反应。LPS注射后2小时，我们测量了一系列炎性细胞因子的血浆浓度。LPS注射后24小时，我们测量了主要大鼠急性期蛋白的肝脏mRNA表达和血清浓度。
喂食EtOH的大鼠肝脏要么没有组织病理学变化，要么有不同程度的脂肪变性。喂食EtOH使主要急性期蛋白α2-巨球蛋白（α2M）的肝脏自发mRNA表达降低了30%（p<0.01）。LPS立即使两个喂食组的血浆肿瘤坏死因子-α和白细胞介素-6增加了100倍以上（p<0.001，所有），在喂食EtOH的大鼠中增加了约两倍（分别为p<0.05和p=0.08）。LPS还诱导了两个喂食组中（α2M）、触珠蛋白、α1-酸性糖蛋白和lipocalin-2肝脏mRNA表达水平和血清浓度的可变但显著的放大（p≤0.01至0.001）。然而，LPS诱导的血清（α2M）和触珠蛋白增加在喂食EtOH的大鼠中不太明显，平均约为配对喂食大鼠浓度的60%（分别为p<0.01和p<0.001）。
大鼠长期暴露于EtOH会降低（α2M）的肝脏自发mRNA表达，并显著损害肝脏对内毒素的急性期反应，尽管促炎细胞因子释放增加。同样的现象可能导致长期过量饮酒的人类对感染的易感性增加。
