Hypoxia potentiates transforming growth factor-β expression of hepatocyte during the cirrhotic condition in rat liver

• Published in: Liver international 2004-12, Vol.24 (6), p.658-668
• Main Authors: Jeong, Won-II, Do, Sun-Hee, Yun, Hae-Sun, Song, Byoung-Joon, Kim, Seong-Jin, Kwak, Wie-Jong, Yoo, Sung-Eun, Park, Ho-Yong, Jeong, Kyu-Shik
• Format: Article
• Language: English
• Subjects: Animals; Carbon Tetrachloride; Cells, Cultured; cirrhosis; Collagen - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Hepatocytes - physiology; Hypoxia; Immunoblotting; Immunohistochemistry; liver; Liver Cirrhosis, Experimental - metabolism; Liver Cirrhosis, Experimental - pathology; Male; myofibroblast; Probability; Rats; Rats, Wistar; Receptors, Transforming Growth Factor beta - analysis; Receptors, Transforming Growth Factor beta - metabolism; Reference Values; RNA, Messenger - blood; Sensitivity and Specificity; smad protein; Smad2 Protein; Smad3 Protein; Trans-Activators - genetics; Trans-Activators - metabolism; transforming growth factor beta
• ISSN: 1478-3223; 1478-3231
• DOI: 10.1111/j.1478-3231.2004.0961.x

: Background/Aims: Many studies have reported that hypoxia might be associated with angiogenesis and fibrogenesis, and the level of transforming growth factor‐β1 (TGF‐β1) was increased in fibrotic liver and maximal at cirrhosis. Therefore, we examined the expression of TGF‐β1, phosphorylated‐Smad2/3 (p‐Smad2/3) of the TGF‐β 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‐β1 was mainly produced by hypoxic hepatocytes at cirrhosis although myofibroblasts (MFBs) and macrophages producing TGF‐β1 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‐β1 expression in hepatocytes might have been associated with hypoxia. Conclusions: We put forward the hypothesis that TGF‐β1 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.