Inhibition of heme oxygenase ameliorates sepsis-induced liver dysfunction in rats.
OBJECTIVE
The disintegration of heme produces carbon monoxide (CO), a known vasodilator, which is catalyzed by heme oxygenase (HO). This study aimed to clarify the effect of HO inhibition on septic rat livers using two types of HO inhibitors; Sn-protoporphyrin (Sn-PP) and Zn-protoporphyrin (Zn-PP).


METHODS
Sepsis was induced in male Sprague-Dawley rats by cecal ligation and puncture (CLP). Either NaOH or HO inhibitors were injected intraperitoneally; first 18 h prior to CLP, then immediately after CLP. The animals were killed 12 and 24 h after CLP and the liver tissue and plasma were harvested.


RESULTS
Using Northern blotting, we found that mRNA of the stress-inducible isozyme, HO-1, was dramatically induced 12 h after CLP. Administering the HO inhibitors, Sn-PP and Zn-PP (5 micromol/kg), induced a significant inhibition of the elevation of aspartate aminotransferase plasma levels, the elevation of cyclic guanosine monophosphete (cGMP) in the liver tissue, and the increase in the sinusoidal space ratio, 24 h after CLP. Both Sn-PP and Zn-PP decreased the mortality rate 24 h after CLP compared with normal saline.


CONCLUSIONS
CO produced by excessively induced HO-1 after CLP promotes an immoderate dilation of the sinusoidal space through the up-regulation of cGMP, resulting in liver dysfunction. Therefore, administering HO inhibitors at appropriate doses could be beneficial for the amelioration of sepsis-induced liver dysfunction.
Iwasashi
Hajime
H
Department of Surgery, Division of Gastroenterological Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Suzuki
Masanori
M
Unno
Michiaki
M
Utiyama
Tetsuyuki
T
Oikawa
Masaya
M
Kondo
Noriko
N
Matsuno
Seiki
S
D000818:Animals; D002248:Carbon Monoxide / Q000032:analysis; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications*
D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D002248:Carbon Monoxide; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing)