This Article Order Full text via Infotrieve Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Montosi, G. Articles by Pietrangelo, A. Search for Related Content PubMed PubMed Citation Articles by Montosi, G. Articles by Pietrangelo, A.

American Journal of Pathology, Vol 152, 1319-1326, Copyright © 1998 by American Society for Investigative Pathology

REGULAR ARTICLES

Spatial and temporal dynamics of hepatic stellate cell activation during oxidant-stress-induced fibrogenesis

G Montosi, C Garuti, A Iannone and A Pietrangelo
Department of Internal Medicine, University of Modena, Italy.

In vitro and in vivo studies indicate that oxidant stress is implicated in liver fibrogenesis. However, it is still unknown whether, in vivo, oxidant stress directly affects the hepatic cells responsible for fibrogenesis, ie, the hepatic stellate cells (HSCs). This study was aimed at answering this question by assessing the temporal and spatial relationships between oxidant stress and activation of HSCs in an in vivo model of oxidant-stress-associated fibrogenesis. To this purpose, rats were treated with carbon tetrachloride (CCl4) and livers subjected to in situ perfusion with nitroblue tetrazolium, which, in the presence of superoxide ions, is reduced to an insoluble blue-colored formazan derivative and is readily detectable in the tissue by light microscopy. Moreover, various combinations of in situ hybridization and immunocytochemical analyses were performed. An acute dose of CCl4 caused a transient production of superoxide radicals at 24 hours into pericentral necrotic areas, whereas HSC appearance and expression of collagen mRNA were detectable only at 48 and 72 hours. After chronic CCl4 intoxication, higher levels of oxygen radical production in necrotic areas were detectable along with dramatic and sustained activation of HSCs. However, maximal HSC activation was still delayed as compared with superoxide production. Expression of heme oxygenase, a gene responsive to a variety of oxidant stress mediators, was strongly enhanced by chronic CCl4 administration but remained unchanged in HSCs, both in situ and after isolation of pure HSC fractions from control and CCl4-treated animals. In conclusion, during postnecrotic fibrogenesis, oxidant stress anticipates HSC activation. HSCs do not directly face an oxidant stress while engaged in active fibrogenesis.

This article has been cited by other articles:

				K. Minami, T. Saito, M. Narahara, H. Tomita, H. Kato, H. Sugiyama, M. Katoh, M. Nakajima, and T. Yokoi Relationship between Hepatic Gene Expression Profiles and Hepatotoxicity in Five Typical Hepatotoxicant-Administered Rats Toxicol. Sci., September 1, 2005; 87(1): 296 - 305. [Abstract] [Full Text] [PDF]