Fibrosis of the hepatic subendothelial (Disse) space is a prominent component of the inflammation elicited by ethanol, and appears to correlate with clinically significant liver disease. The lesion consists of a collagen-rich new-matrix that replaces the low- density matrix normally present in this location. In recent and on-going studies from this laboratory, the lipocyte (fat-storing or Ito cell) has been examined in pure primary culture and found to be a major source of several matrix proteins including collagen, laminin and proteoglycans. In vivo, cells referred to as 'myofibroblasts' have been identified following chronic alcohol consumption and localized specifically to areas of fibrogenesis. Morphologic studies suggest that lipocytes and myofibriblasts represent the same cell in various stages of transition. The working hypothesis for the present studies is that ethanol 'activates' lipocytes, causing their conversion from resting, vitamin A-storing cells to matrix-secreting myofibroblasts. The pathway of lipocyte activation is the principal focus of the proposed research. Several possibilities will be explored, including stimulation by acetaldehyde or by soluble mediators of inflammation released as by-products of ethanol metabolism. The first series of experiments will establish wheter lipocyte activation occurs as a direct result of ethanol metabolism. This will be accomplished using a novel cell culture approach, in which hepatocytes and lipocytes are co-cultured as 'microorganoids' and incubated with varying concentrations of ethanol. Additional studies will examine whether lipocyte activation is indirect, involving compounds produced by neutrophils of Kupffer cells previously exposed to conditioned medium from ethanol-treated hepatocytes. Lipocyte activation will be judged with studies of ultrastructure as well as quantitative measurements of matrix protein secretion, matrix gene expression, and cell proliferation. Recently developed methods for evaluating matrix gene expression and for culture of individual parenchymal and non- parenchymal cell populations allow a direct approach to the pathogenesis of this common and important condition.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA007810-02
Application #
3111717
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1988-07-01
Project End
1993-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Hanson, Jennifer C; Bostick, Michele K; Campe, Carson B et al. (2006) Transgenic overexpression of interleukin-8 in mouse liver protects against galactosamine/endotoxin toxicity. J Hepatol 44:359-67
Xu, Junquan; Lee, Gene; Wang, Haimei et al. (2004) Limited role for CXC chemokines in the pathogenesis of alpha-naphthylisothiocyanate-induced liver injury. Am J Physiol Gastrointest Liver Physiol 287:G734-41
Maher, Jacquelyn J (2002) Alcoholic steatosis and steatohepatitis. Semin Gastrointest Dis 13:31-9
Bjorkegren, Johan; Beigneux, Anne; Bergo, Martin O et al. (2002) Blocking the secretion of hepatic very low density lipoproteins renders the liver more susceptible to toxin-induced injury. J Biol Chem 277:5476-83
Faouzi, S; Burckhardt, B E; Hanson, J C et al. (2001) Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-kappa B-independent, caspase-3-dependent pathway. J Biol Chem 276:49077-82
Sonda, S; Ting, L M; Novak, S et al. (2001) Cholesterol esterification by host and parasite is essential for optimal proliferation of Toxoplasma gondii. J Biol Chem 276:34434-40
Maher, J J (2001) Interactions between hepatic stellate cells and the immune system. Semin Liver Dis 21:417-26
Saito, J M; Maher, J J (2000) Bile duct ligation in rats induces biliary expression of cytokine-induced neutrophil chemoattractant. Gastroenterology 118:1157-68
Maher, J J (1999) Leukocytes as modulators of stellate cell activation. Alcohol Clin Exp Res 23:917-21
Maher, J J (1999) Cytokines: overview. Semin Liver Dis 19:109-15

Showing the most recent 10 out of 23 publications