Regular Article
Inhibition of Kupffer Cells Reduced CXC Chemokine Production and Liver Injury

https://doi.org/10.1006/jsre.2001.6217Get rights and content

Abstract

Background. Cytokine production is a critical component of ischemia/reperfusion (IR) injury. In the liver, Kupffer cells produce cytokines and chemokines (i.e., cytokines with chemoattractant properties) that are important mediators in neutrophil recruitment and subsequent hepatocellular injury. Therefore, the role of Kupffer cells in chemokine production in hepatic IR injury was investigated.

Methods. Adult male C57BL/6 mice underwent 90 min of partial hepatic ischemia followed by various reperfusion times (i.e., 0, 1.5, 3, and 6 h). Gadolinium chloride (GC), which inhibits Kupffer cell activity, was administered to mice 48 and 24 h prior to ischemia. The control group received a corresponding volume of normal saline. Plasma levels of the cytokine macrophage inflammatory protein-2 (MIP-2), KC, and tumor necrosis factor (TNF)-α and liver mRNA were measured. Liver injury was assessed by plasma level of alanine transaminase (ALT) and histopathology.

Results. A reperfusion time-dependent liver injury occurred as indicated by increased levels of plasma ALT and histopathology. The injury was associated with increased plasma TNF-α, MIP-2, and KC and their hepatic mRNA expression and neutrophil infiltration into ischemic lobes of the liver. GC treatment significantly reduced the number of Kupffer cells as determined by the immunostained liver tissue sections. The extent of liver injury significantly decreased in GC-treated mice that were associated with decreased levels of plasma ALT, TNF-α, MIP-2, and KC and neutrophil infiltration.

Conclusions. This study suggests that Kupffer cells are major contributors to cytokine production in hepatic IR and their modulation may serve as a potential target for therapeutic intervention.

References (33)

  • S. Todo et al.

    Primary nonfunction of hepatic allografts with preexisting fatty infiltration

    Transplantation

    (1989)
  • S.H. Belle et al.

    Liver transplantation in the United States: 1988 to 1990

    Clin. Transpl.

    (1991)
  • L.M. Colletti et al.

    Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat

    J. Clin. Invest.

    (1990)
  • H. Jaeschke et al.

    Superoxide generation by Kupffer cells and priming of neutrophils during reperfusion after hepatic ischemia

    Free Radic. Res. Commun.

    (1991)
  • H. Jaeschke et al.

    Reactive oxygen species during ischemia–reflow injury in isolated perfused rat liver

    J. Clin. Invest.

    (1988)
  • D.G. Remick et al.

    Cytokines and extrahepatic sequelae of ischemic–reperfusion injury to the liver

    Ann. N. Y. Acad. Sci.

    (1994)
  • Cited by (0)

    1

    To whom correspondence should be addressed at Department of Surgery, B-424 Clinical Center, Michigan State University, East Lansing, MI, 48824-1315. Fax: 517-353-6392. E-mail: [email protected].

    View full text