Prolyl 4-hydroxylase inhibitor (HOE 077) inhibits pig serum-induced rat liver fibrosis by preventing stellate cell activation.
OBJECTIVE
The aim of this study was to investigate the effect and mechanism of fibrosuppression by a newly synthesized prolyl 4-hydroxylase inhibitor [HOE 077, 2, 4-pyridine dicarboxylic acid bis [(2-methoxyethyl) amide]] on pig serum-induced liver fibrosis in the rat.


METHODS
Male Wistar rats received 0.5 ml of pig serum twice a week for 10 weeks with 0, 100 or 200 ppm of HOE 077. At the end of the experiment, the hydroxyproline content of the liver, and alanine aminotransferase were measured. Histological stains used were HE, azan and a stain for alpha-smooth muscle actin (alpha-SMA). Electron microscopy was also performed. Messenger RNA expressions of type I and III procollagen were examined by Northern blot analysis. alpha-SMA positive cells and fibers with azan staining were assessed as percent area of the tissue specimen, using an image analysis system.


RESULTS
Rats that received pig serum for 10 weeks showed an increased liver hydroxyproline content of 318+/-39 microg/g wet weight (n=15). HOE 077 at doses up to 200 ppm significantly (p<0.01) reduced this increase of liver hydroxyproline content (181+/-39 microg/g wet weight, n=15) in accordance with improved histological findings. 200 ppm of HOE 077 significantly reduced mRNA expressions of alpha2(I) (486+/-102 vs 151+/-36, p<0.01) and alpha1(III) (276+/-127 vs 160+/-67, p<0.05) procollagen and percent area of alpha-SMA positive cells (2.94+/-2.14 vs 1.17+/-0.88%). Electron microscopy revealed that 200 ppm of HOE 077 prevented the loss of fat droplets.


CONCLUSIONS
A prolyl 4-hydroxylase inhibitor (HOE 077) prevented pig serum-induced rat liver fibrosis by inhibiting stellate cell activation.
Matsumura
Y
Y
First Department of Internal Medicine, Yamaguchi University, School of Medicine, Japan.
Sakaida
I
I
Uchida
K
K
Kimura
T
T
Ishihara
T
T
Okita
K
K
D000818:Animals; D015415:Biomarkers / Q000097:blood; D001769:Blood; D015152:Blotting, Northern; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006909:Hydroxyproline / Q000037:antagonists & inhibitors; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008854:Microscopy, Electron; D016253:Microscopy, Immunoelectron; D011347:Procollagen / Q000037:antagonists & inhibitors; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013552:Swine
D015415:Biomarkers; D004791:Enzyme Inhibitors; D011347:Procollagen; D011725:Pyridines; D012333:RNA, Messenger; C074630:lufironil; D011393:Procollagen-Proline Dioxygenase; D006909:Hydroxyproline