Increased susceptibility to liver injury after hemorrhagic shock in rats chronically fed ethanol: role of nuclear factor-kappa B, interleukin-6, and granulocyte colony-stimulating factor.
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-kappa B (NF-kappa B), 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-kappa B 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-kappa B 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-kappa B 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.
Ono
Masafumi
M
Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Yu
Bi
B
Hardison
Edith G
EG
Mastrangelo
Mary-Ann A
MA
Tweardy
David J
DJ
D000818:Animals; D001784:Blood Gas Analysis; D016207:Cytokines / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology*; D006519:Hepatitis, Alcoholic / Q000473:pathology; D015850:Interleukin-6 / Q000502:physiology*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008168:Lung / Q000378:metabolism; D008297:Male; D009102:Multiple Organ Failure / Q000209:etiology; D016328:NF-kappa B / Q000502:physiology*; D011014:Pneumonia / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000150:complications / Q000378:metabolism / Q000473:pathology*
D016207:Cytokines; D015850:Interleukin-6; D016328:NF-kappa B; D016179:Granulocyte Colony-Stimulating Factor; D000431:Ethanol