Prevention of severe toxic liver injury and oxidative stress in MCP-1-deficient mice.
OBJECTIVE
Administration of carbon tetrachloride determines liver injury, inflammation and oxidative stress, but the molecular mechanisms of damage are only partially understood. In this study, we investigated the development of acute toxic damage in mice lacking monocyte chemoattractant protein-1 (MCP-1), a chemokine which recruits monocytes and activated lymphocytes.


METHODS
Mice with targeted deletion of the MCP-1 gene and wild type controls were administered a single intragastric dose of carbon tetrachloride. Serum liver enzymes, histology, expression of different chemokines and cytokines, and intrahepatic levels of oxidative stress-related products were evaluated.


RESULTS
Compared to wild type mice, peak aminotransferase levels were significantly lower in MCP-1-deficient animals. This was paralleled by a delayed appearance of necrosis at histology. In addition, MCP-1-deficient mice showed a shift in the pattern of infiltrating inflammatory cells, with a predominance of polymorphonuclear leukocytes. Lack of MCP-1 was also accompanied by reduced intrahepatic expression of cytokines regulating inflammation and tissue repair. The increase in tissue levels of reactive oxygen species and 4-hydroxy-nonenal following administration of the hepatotoxin was also significantly lower in animals lacking MCP-1.


CONCLUSIONS
Lack of MCP-1 affords protection from damage and development of oxidative stress in a toxic model of severe acute liver injury.
Zamara
Elena
E
Dipartimento di Medicina e Oncologia Sperimentale, University of Turin, Italy.
Galastri
Sara
S
Aleffi
Sara
S
Petrai
Ilaria
I
Aragno
Manuela
M
Mastrocola
Raffaella
R
Novo
Erica
E
Bertolani
Cristiana
C
Milani
Stefano
S
Vizzutti
Francesco
F
Vercelli
Alessandro
A
Pinzani
Massimo
M
Laffi
Giacomo
G
LaVilla
Giorgio
G
Parola
Maurizio
M
Marra
Fabio
F
D000447:Aldehydes / Q000032:analysis; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D018932:Chemokine CCL2 / Q000235:genetics*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils; D018384:Oxidative Stress / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism
D000447:Aldehydes; D018932:Chemokine CCL2; D016207:Cytokines; D017382:Reactive Oxygen Species; D002251:Carbon Tetrachloride; C027576:4-hydroxy-2-nonenal