Nitric oxide synthase inhibition and the induction of cytochrome P-450 affect heme oxygenase-1 messenger RNA expression after partial hepatectomy and acute inflammation in rats.
OBJECTIVE
a) To evaluate in vivo, in rat liver, heme oxygenase-1 (HO-1) messenger RNA (mRNA) expression level and the regulation of 3',5'-cyclic guanosine monophosphate (cGMP) production during hepatic regeneration, localized inflammation, and systemic inflammation; and b) to investigate the effect of the induction of cytochrome P-450 and nitric oxide synthase (NOS) inhibition on HO-1 mRNA level and cGMP production in the liver.


METHODS
Experimental, comparative study.


METHODS
Biochemical and molecular biology laboratory.


METHODS
Six-wk-old male Sprague-Dawley rats (n = 60).


METHODS
We randomly divided the rats into four groups: a) saline controls; b) animals receiving lipopolysaccharide (600 microg/kg) for systemic inflammation; c) animals receiving turpentine oil (5 mL/kg) for localized inflammation obtained by sterile abscess; and d) partially hepatectomized animals (two-thirds removal of the parenchyma) for hepatic regeneration.


RESULTS
Hepatic regeneration induced HO-1 mRNA expression, as shown by quantitative reverse transcription-polymerase chain reaction analysis. The time course of liver HO-1 mRNA induction after partial hepatectomy and localized and systemic inflammation showed a similar and gradual increase, with a maximum at 6 hrs and a return to a minimal level 48 hrs after treatments. Liver HO-1 mRNA was overexpressed during localized vs. systemic inflammation. This overexpression was not correlated with either serum IL-6 or corticosterone concentrations, but is related to increased cGMP production. The administration of phenobarbital, a cytochrome P-450 inducer and of nitro-L-arginine methyl ester, a NOS inhibitor, prevented cGMP production and abolished the overexpression of HO-1 mRNA.


CONCLUSIONS
The results of this study indicate that HO-1 mRNA is induced during hepatic regeneration with a similar time course to that observed during acute inflammation. In addition, we demonstrated that: a) HO-1 mRNA is overexpressed during localized vs. systemic inflammation; b) this overexpression is not correlated with IL-6 or corticosterone concentrations but is related to intrahepatic cGMP production; c) induction of cytochromes P-450 and/or inhibition of NOS both reduce liver cGMP production and HO-1 mRNA expression. These results suggest that in rat liver, a cGMP-transducing pathway may control HO-1 mRNA expression. Thus, there may be a role for HO-1 mRNA in the modulation of the hepatic stress response.
Institut National de la Santé et de la Recherche Médicale, INSERM U-78, Bois-Guillaume, France.
S
S
Lyoumi
H
H
Puy
F
F
Tamion
M
M
Scotté
M
M
Daveau
Y
Y
Nordmann
J P
JP
Lebreton
J C
JC
Deybach
D000208:Acute Disease; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology*; D004195:Disease Models, Animal; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics* / Q000276:immunology*; D051547:Heme Oxygenase-1; D006498:Hepatectomy; D007249:Inflammation / Q000276:immunology; D008070:Lipopolysaccharides; D008115:Liver Regeneration / Q000276:immunology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018746:Systemic Inflammatory Response Syndrome / Q000276:immunology*; D014425:Turpentine
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D014425:Turpentine