Pressure loading and ethanol exposure differentially modulate rat hepatic stellate cell activation

✍ Scribed by Yoshikiyo Okada; Yoshikazu Tsuzuki; Ryota Hokari; Jyunichi Miyazaki; Koji Matsuzaki; Norikazu Mataki; Shunsuke Komoto; Chikako Watanabe; Atsushi Kawaguchi; Shigeaki Nagao; Kazuro Itoh; Soichiro Miura

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 393 KB
• Volume: 215
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.21329

✦ Synopsis

Abstract

Ethanol may cause an increase in sinusoidal pressure accompanied by portal hypertension. Hepatic stellate cells (HSCs) located in hepatic sinusoids may therefore be frequently exposed to dual stimulations of mechanical pressure and ethanol exposure in alcoholic liver injury. In this study, the effects of pressure loading and ethanol exposure on activation of rat cultured HSCs were investigated using an in vitro pressure‐inducing apparatus. HSCs were cultured in media containing ethanol (0–100 mM) under different pressures (1–40 mmHg). Morphological changes and migration index were determined. We also determined the expression levels of α‐smooth muscle actin (α‐SMA) and mitogen‐activated protein kinases (MAPKs) by Western blot analysis and the level of collagen IV and transforming growth factor β1 (TGF‐β1) by ELISA. Pressure loading alone induced up‐regulation of α‐SMA via the extracellular signal‐regulated kinases 1 and 2 (ERK1/2) and c‐jun N‐terminal kinase (JNK) signaling pathways, prolonged extension of marginal length, and increased production of collagen IV. In contrast, ethanol exposure alone increased only extension of marginal length and cell migration. Dual stimulations of pressure loading and ethanol exposure enhanced the production of TGF‐β1 and migration index. The TGF‐β1‐dependent p38 MAPK pathway may operate for production of extracellular matrix (ECM) or enhanced migration in the case of dual stimulations. In conclusion, static pressure loading is an important factor directly accelerating the activation of HSCs. Although increased sinusoidal pressure and ethanol exposure might differentially modulate HSC activation, both stimuli are involved in an additive manner in some situations. J. Cell. Physiol. 215: 472–480, 2008. © 2007 Wiley‐Liss, Inc.