Thioacetamide-induced liver regeneration involves the expression of cyclooxygenase 2 and nitric oxide synthase 2 in hepatocytes.
OBJECTIVE
A regeneration process intended to restore organ function follows liver hepatotoxicity induced by a necrogenic dose of thioacetamide (TAM).


METHODS
The expression of genes related to inflammation such as nitric oxide synthase-2 (NOS-2) and cyclooxygenase-2 (COX-2) has been analyzed in the course of the regenerative response, using NOS-2 KO mice or animals treated with selective inhibitors of COX-2.


RESULTS
All animals lacking both activities survived to the hepatotoxic administration. However, animals deficient for NOS-2 exhibited more severe organ damage in view of the levels of hepatic serum markers of function, as well as an attenuated activation of NF-kappaB. The levels of C/EBPs were determined as markers of hepatocyte de-differentiation and regeneration, and the expression of COX-2 in TAM treated animals was concomitant with a decrease in C/EBP-alpha level. Analysis of cyclin D1, E and PCNA correlated with hepatocytes entering into the S phase of cell cycle by the effect of TAM.


CONCLUSIONS
These data indicate that hepatocytes from TAM-treated mice express NOS-2 and COX-2 proteins and initiate the regeneration process that follows acute liver injury. However, the absence of NO delays hepatocyte regeneration, whereas COX-2-inhibition appears to decrease liver damage.
Fernández-Martínez
Amalia
A
Instituto de Bioquímica, Centro Mixto CSIC-UCM, and Centro Nacional de Investigaciones Cardiovasculares, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain.
Callejas
Nuria A
NA
Casado
Marta
M
Boscá
Lisardo
L
Martín-Sanz
Paloma
P
D000818:Animals; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D002273:Carcinogens / Q000494:pharmacology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D017353:Gene Deletion; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008111:Liver Function Tests; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013853:Thioacetamide / Q000494:pharmacology*
D029742:Caenorhabditis elegans Proteins; D002273:Carcinogens; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; C400703:nos-2 protein, C elegans; D013853:Thioacetamide; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases