Shock. 21(6):519-525, JUNE 2004
DOI: 10.1097/01.shk.0000126905.75237.07
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PMID: 15167680
Issn Print: 1073-2322
Publication Date: June 2004
INCREASED SUSCEPTIBILITY TO LIVER INJURY AFTER HEMORRHAGIC SHOCK IN RATS CHRONICALLY FED ETHANOL: ROLE OF NUCLEAR FACTOR-κB, INTERLEUKIN-6, AND GRANULOCYTE COLONY-STIMULATING FACTOR
Masafumi Ono;Bi Yu;Edith Hardison;Mary-Ann Mastrangelo;David Tweardy;
+ Author Information
Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030
Abstract
Chronic ethanol use preceding severe trauma and hemorrhagic shock (HS) is associated with an increased incidence of multiorgan failure (MOF) and death; however, the molecular basis for this increased susceptibility is unknown. We previously demonstrated that production of interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF), mediated by nuclear factor-κB (NF-κB), each make essential contributions to organ injury and inflammation in a rodent model of controlled HS, and we proposed in this study to examine the hypothesis that the increased susceptibility to MOF after shock/trauma in the setting of chronic ethanol use is due to an exaggerated activation of NF-κB and production of these proinflammatory cytokines. We observed increased HS-induced liver injury 4 h after resuscitation in rats fed the ethanol-containing Lieber-DeCarli liquid diet for 8 weeks compared with rats fed the control liquid diet (3-fold increase in serum alanine aminotransferase [ALT], P = 0.008, and 2-fold increase in focal liver necrosis, P = 0.005). The increased liver injury in the ethanol-fed HS rats was accompanied by a 70% increase in liver NF-κB activation (P < 0.05), a 3- to 5-fold increase in hepatocyte and Kupffer cell production of IL-6 and G-CSF (P < 0.05 for each), and a 2-fold increase in neutrophil infiltration (P < 0.005) compared with the control diet-fed HS rats. Thus, increased susceptibility to HS-induced liver injury in the setting of chronic ethanol use may be mediated, at least in part, by increased NF-κB activation resulting in increased local production of IL-6 and G-CSF and increased infiltration of neutrophils, which can damage liver cells directly and contribute to impaired sinusoidal blood flow.
