Tacrolimus modulates liver and pancreas nitric oxide synthetase and heme-oxygenase isoforms and cytokine production after endotoxemia.
Cytoprotective effects of tacrolimus are due to its unspecific anti-inflammatory and anti-oxidant properties. Neither the exact mechanisms nor if there is any organ-specificity or dose-dependent response have not been yet elucidated. Our aim was to evaluate the effect of tacrolimus on oxidative stress and mediator production in liver and pancreatic tissue secondary to endotoxemia. Wistar rats were pretreated with intraperitoneal injection of tacrolimus (0.07, 0.15, and 0.3mg/kg) 24h before Escherichia coli LPS was administrated. Animals were sacrificed 24h after LPS administration and iNOS, eNOS, and nNOS and type 1 and 2 heme-oxygenase (HO) expression were measured. TNF-α and IL-1 tissue expression and plasmatic NO, CO, TNF-α, and IL-1 were also determined. LPS exposure increased iNOS expression in both organs, eNOS did not show variations and liver nNOS expression was significantly lower. Tacrolimus diminished both pancreas and liver iNOS and nNOS expression. Both liver and pancreatic eNOS expression augmented when tacrolimus was administrated. High doses of tacrolimus were correlated with ameliorated liver HO-1 plus HO-2 and pancreas HO-1 expression after LPS stimulation. Tacrolimus treatment diminished TNF-α but not IL-1 expression increase after LPS challenge in hepatic tissue. Pancreatic TNF-α and IL-1 values diminished partially when high doses were employed. Plasmatic NO, CO, TNF-α, and IL-1 concentrations increase after LPS challenge was diminished when highest doses of tacrolimus were given. In conclusion, tacrolimus exerts a protective effect on commonly observed harmful phenomena after LPS stimulation by modulating liver and pancreas oxidative enzyme expression and cytokine production.
Department of Surgery, Germans Trias i Pujol Hospital, Universitat Autònoma, Ctra Del Canyet s/n, 08916 Badalona, Barcelona, Spain. balibrea@gmail.com
José M
JM
Balibrea
M Cruz
MC
García-Martín
Sara
S
Cuesta-Sancho
Yoko
Y
Olmedilla
Javier
J
Arias-Díaz
Elena
E
Fernández-Sevilla
Elena
E
Vara
José L
JL
Balibrea
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D019446:Endotoxemia / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006419:Heme Oxygenase (Decyclizing) / Q000737:chemistry / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000378:metabolism; D010179:Pancreas / Q000201:enzymology / Q000378:metabolism; D020033:Protein Isoforms; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000494:pharmacology*
D016207:Cytokines; D007166:Immunosuppressive Agents; D020033:Protein Isoforms; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); D016559:Tacrolimus