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Inhibition of heme oxygenase ameliorates sepsis-induced liver dysfunction in rats
Hajime Iwasashi1, Masanori Suzuki, Michiaki Unno
1Department of Surgery, Division of Gastroenterological Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.
Purpose:
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.