Hypoxia potentiates transforming growth factor-beta expression of hepatocyte during the cirrhotic condition in rat liver.
OBJECTIVE
Many studies have reported that hypoxia might be associated with angiogenesis and fibrogenesis, and the level of transforming growth factor-beta1 (TGF-beta1) was increased in fibrotic liver and maximal at cirrhosis. Therefore, we examined the expression of TGF-beta1, phosphorylated-Smad2/3 (p-Smad2/3) of the TGF-beta immediate down stream signaling system and hypoxic status during hepatic fibrogenesis.


METHODS
Fibrosis of rats was induced by carbon tetrachloride. Collagens were detected with Azan stain. Immunohistochemistry and immunoblotting was used.


RESULTS
TGF-beta1 was mainly produced by hypoxic hepatocytes at cirrhosis although myofibroblasts (MFBs) and macrophages producing TGF-beta1 were decreased. Moreover, distribution of p-Smad2/3 in hepatocytes was consistent with those of hypoxic hepatocytes regardless of MFBs. Furthermore, in recovery, most MFBs disappeared, whereas positive reactions of p-Smad2/3 still existed in the hepatocytes of hypoxic areas. Therefore, TGF-beta1 expression in hepatocytes might have been associated with hypoxia.


CONCLUSIONS
We put forward the hypothesis that TGF-beta1 is mainly produced by MFBs and macrophages at early and middle stages of fibrotic processes, but it is predominantly released by hypoxic hepatocytes in the last fibrotic stage or cirrhosis.
Jeong
Won-Ii
WI
College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea.
Do
Sun-Hee
SH
Yun
Hae-Sun
HS
Song
Byoung-Joon
BJ
Kim
Seong-Jin
SJ
Kwak
Wie-Jong
WJ
Yoo
Sung-Eun
SE
Park
Ho-Yong
HY
Jeong
Kyu-Shik
KS
D000818:Animals; D002251:Carbon Tetrachloride; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000502:physiology*; D000860:Hypoxia; D015151:Immunoblotting; D007150:Immunohistochemistry; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D011336:Probability; D012333:RNA, Messenger / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism*; D012016:Reference Values; D012680:Sensitivity and Specificity; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D015534:Trans-Activators; D003094:Collagen; D002251:Carbon Tetrachloride