Immunosuppressants decrease neutrophil chemoattractant and attenuate ischemia/reperfusion injury of the liver in rats.
BACKGROUND
Neutrophils may play an important role in the development of liver ischemia/reperfusion injury. We investigated the effects of the immunosuppressants azathioprine (AZA), cyclosporine A (CsA), tacrolimus (FK506), and rapamycin (RPM) on the expression of cytokine-induced neutrophil chemoattractant (CINC) after ischemia/reperfusion of the liver.


METHODS
Liver ischemia was induced in male Wistar rats by occluding the portal vein with a microvascular clip for 30 minutes. Rats received two intramuscular injections of AZA (4 mg/kg), CsA (5 mg/kg), FK506 (0.5 mg/kg), or RPM (0.5 mg/kg) 3 and 24 hours before ischemia/reperfusion of the liver.


RESULTS
Serum CINC concentrations in untreated animals increased, peaked 6 hours after reperfusion, and thereafter decreased gradually. Pretreatment with AZA, CsA, FK506, and RPM, however, inhibited the increase in serum CINC concentrations after reperfusion. CINC mRNA in liver tissue increased and peaked 3 hours after reperfusion, but was significantly lower in animals treated with AZA, CsA, FK506, and RPM. In vitro CINC production by Kupffer cells harvested from animals treated with AZA, CsA, FK506, or RPM 3 hours after reperfusion was also significantly lower than that observed in untreated animals. Both myeloperoxidase activity and the number of neutrophils accumulating in the liver 24 hours after reperfusion in animals treated with AZA, CsA, FK506, and RPM were significantly lower than in untreated animals. This correlated with lower serum aspartate transaminase, alanine transaminase, and lactate dehydrogenase levels in animals treated with AZA, CsA, FK506, and RPM 24 hours after reperfusion.


CONCLUSIONS
The immunosuppressants AZA, CsA, FK506, and RPM reduce neutrophil accumulation and attenuate ischemia/reperfusion injury of the liver.
Matsuda
T
T
Department of Surgery II, Kumamoto University Medical School, Honjo, Japan.
Yamaguchi
Y
Y
Matsumura
F
F
Akizuki
E
E
Okabe
K
K
Liang
J
J
Ohshiro
H
H
Ichiguchi
O
O
Yamada
S
S
Mori
K
K
Ogawa
M
M
D000818:Animals; D001379:Azathioprine / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D007166:Immunosuppressive Agents / Q000276:immunology / Q000627:therapeutic use*; D019410:Interleukin-16 / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000098:blood supply*; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D011090:Polyenes / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D020123:Sirolimus; D016559:Tacrolimus / Q000627:therapeutic use; D013997:Time Factors
D007166:Immunosuppressive Agents; D019410:Interleukin-16; D011090:Polyenes; D016572:Cyclosporine; D001379:Azathioprine; D020123:Sirolimus; D016559:Tacrolimus