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


Professor Kyu-Shik Jeong, DVM, PhD, College of Veterinary Medicine, Kyungpook National University, Daegu City 702-701, South Korea.
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Abstract: 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.