title: Long-Term Ethanol Exposure Decreases the Endotoxin-Induced Hepatic Acute Phase Response in Rats.
abstract: 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.
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Emilie
authors.initials: E
authors.lastname: Glavind
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Vilstrup
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Henning
authors.initials: H
authors.lastname: Grønbaek
authors.affiliation: Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hamilton-Dutoit
authors.affiliation: Medical Research Laboratory, Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Nils Erik
authors.initials: NE
authors.lastname: Magnusson
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Karen Louise
authors.initials: KL
authors.lastname: Thomsen
mesh_terms: D000209:Acute-Phase Proteins / Q000096:biosynthesis*; D000210:Acute-Phase Reaction / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D004731:Endotoxins / Q000633:toxicity*; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000209:Acute-Phase Proteins; D004731:Endotoxins; D018836:Inflammation Mediators; D000431:Ethanol
keywords: Acute-Phase Response; Alpha-2-Macroglobulin; Endotoxin; Ethanol; Rats