Fibrosis is the liver's response to diverse injuries. Representing parenchymal """"""""scar"""""""", it consists of collagens and other large extracellular matrix (ECM) proteins. The effects of fibrosis are both regional and local, involving disruption of lobular structure and also cellular function. Fibrosis in its advanced form, cirrhosis, is the most important cause of morbidity and mortality from liver disease. When this project began, in 1982, its goal was defining the cellular source(s) of fibrosis, as an essential first step towards understanding its regulation. This was accomplished through development of methods for mass isolation and primary culture of the individual cell populations of the liver. The lipocyte (Ito or fat-storing cell) emerged as the principal fibrogenic cell type. It was found, moreover, to undergo activation, defined as a pleiotypic response to inflammation. In this response, lipocytes convert from a normally quiescent, retinoid-storing state to one in which ECM production is sharply upregulated and features of smooth-muscle cells appear, including contraction. During the recent period of funding, our focus has been the regulation of lipocyte activation. While soluble mediators of inflammation (cytokines) are in part responsible, the role of the BCM itself is, if anything, more important than that of individual cytokines. In pursuing the lipocyte-activating effect of ECM, we have investigated fibronectin in detail, finding that a splice variant, one containing the EIIIA segment, plays a critical role. Production of this form increases sharply within 12 hours of an injury and is localized specifically to sinusoidal endothelial cells. In culture the EIIIA-containing form (A+-fibronectin) has direct lipocyte-activating effects, which are completely neutralized by a monoclonal antibody to the EIIIA segment. The-major goal of this continuation proposal is to extend these observations with studies of: (1) the impact of the inflammatory milieu on the lipocyte activating effect of the fibronectin EIIIA segment: elements to be examined include other variable segments in the -fibronectin molecule, soluble mediators of inflammation and the ECM context; (2) the minimum domain within EIIIA that is responsible for its activity; (3) the lipocyte receptor that recognizes the EIIIA segment; (4) the effect on fibrogenesis in vivo of anti-EIIIA antibodies or of peptides modeled on the active region of EIIIA; and finally (5) the regulation of endothelial production of A+-fibronectin by soluble mediators of inflammation, particularly transforming growth factor- B. The culmination of this work will be a new approach to therapy for fibrosis, based on competitive inhibition of the EIIIA segment for its lipocyte receptor.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK031198-17
Application #
2734011
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1982-07-01
Project End
2000-06-30
Budget Start
1998-07-15
Budget End
1999-06-30
Support Year
17
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Wang, Bruce; Dolinski, Brian M; Kikuchi, Noriko et al. (2007) Role of alphavbeta6 integrin in acute biliary fibrosis. Hepatology 46:1404-12
Kikuchi, Shojiro; Griffin, Courtney T; Wang, Shao-Shean et al. (2005) Role of CD44 in epithelial wound repair: migration of rat hepatic stellate cells utilizes hyaluronic acid and CD44v6. J Biol Chem 280:15398-404
Chang, Ming-Ling; Chen, Jeng-Chang; Alonso, Claudio R et al. (2004) Regulation of fibronectin splicing in sinusoidal endothelial cells from normal or injured liver. Proc Natl Acad Sci U S A 101:18093-8
George, J; Wang, S S; Sevcsik, A M et al. (2000) Transforming growth factor-beta initiates wound repair in rat liver through induction of the EIIIA-fibronectin splice isoform. Am J Pathol 156:115-24
Roulot, D; Sevcsik, A M; Coste, T et al. (1999) Role of transforming growth factor beta type II receptor in hepatic fibrosis: studies of human chronic hepatitis C and experimental fibrosis in rats. Hepatology 29:1730-8
George, J; Roulot, D; Koteliansky, V E et al. (1999) In vivo inhibition of rat stellate cell activation by soluble transforming growth factor beta type II receptor: a potential new therapy for hepatic fibrosis. Proc Natl Acad Sci U S A 96:12719-24
McDonagh, A F; Bissell, D M (1998) Porphyria and porphyrinology--the past fifteen years. Semin Liver Dis 18:3-15
Wang, Y J; Wang, S S; Bickel, M et al. (1998) Two novel antifibrotics, HOE 077 and Safironil, modulate stellate cell activation in rat liver injury: differential effects in males and females. Am J Pathol 152:279-87
Racine-Samson, L; Rockey, D C; Bissell, D M (1997) The role of alpha1beta1 integrin in wound contraction. A quantitative analysis of liver myofibroblasts in vivo and in primary culture. J Biol Chem 272:30911-7
Rockey, D C; Chung, J J (1995) Inducible nitric oxide synthase in rat hepatic lipocytes and the effect of nitric oxide on lipocyte contractility. J Clin Invest 95:1199-206

Showing the most recent 10 out of 23 publications