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Critical role of CXC chemokines in endotoxemic liver injury in mice
Author(s) -
Li Xiang,
Klintman Daniel,
Liu Qing,
Sato Tohru,
Jeppsson Bengt,
Thorlacius Henrik
Publication year - 2004
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0603297
Subject(s) - chemokine , intravital microscopy , lipopolysaccharide , liver injury , inflammation , biology , immunology , chemotaxis , leukocyte trafficking , cytokine , microcirculation , pharmacology , medicine , receptor , biochemistry
Tissue accumulation of leukocytes constitutes a rate‐limiting step in endotoxin‐induced tissue injury. Chemokines have the capacity to regulate leukocyte trafficking. However, the role of CXC chemokines, i.e., macrophage inflammatory protein‐2 (MIP‐2) and cytokine‐induced neutrophil chemoattractant (KC), in leukocyte recruitment, microvascular perfusion failure, cellular injury, and apoptosis in the liver remains elusive. Herein, mice were challenged with lipopolysaccharide (LPS) in combination with D‐galactosamine, and intravital microscopy of the liver microcirculation was conducted 6 h later. It was found that immunoneutralization of MIP‐2 and KC did not reduce LPS‐induced leukocyte rolling and adhesion in postsinusoidal venules. In contrast, pretreatment with monoclonal antibodies against MIP‐2 and KC abolished (83% reduction) extravascular recruitment of leukocytes in the livers of endotoxemic mice. Notably, endotoxin challenge increased the expression of CXC chemokines, which was mainly confined to hepatocytes. Moreover, endotoxin‐induced increases of liver enzymes and hepatocellular apoptosis were decreased by more than 82% and 68%, respectively, and sinusoidal perfusion was restored in mice passively immunized against MIP‐2 and KC. In conclusion, this study indicates that intravascular accumulation of leukocytes in the liver is independent of CXC chemokines in endotoxemic mice. Instead, our novel data suggest that CXC chemokines are instrumental in regulating endotoxin‐induced transmigration and extravascular tissue accumulation of leukocytes. Indeed, these findings demonstrate that interference with MIP‐2 and KC functions protects against septic liver damage and may constitute a potential therapeutic strategy to control pathological inflammation in endotoxemia.