The mechanisms responsible for the increased hepatic connective tissue deposition in cirrhosis remain unknown; and there is no established therapy for hepatic fibrosis. In this issue of Hepatology, Ruwart et al. (1) report that 16,16-dimethyl prostaglandin E2 (DMPG) inhibits hepatic collagen deposition, and, therefore, potentially will be effective in the treatment of cirrhosis. This editorial will first review the assembly of extracellular matrix (ECM) proteins and the metabolism of collagens, the most abundant proteins in the ECM. Using this knowledge of connective tissue proteins as a framework, strategies for the therapy of hepatic fibrosis will be discussed.
Fibrogenesis plays an important role in the accumulation of hepatic connective tissue (2-4). In cirrhotic livers, whatever the etiology, fibrogenesis results in a several-fold increase in collagen content (2). Collagen types present in normal livers (I, 111, IV, V and VI) increase together in hepatic fibrogenesis (2, 4, 5), suggesting a coordinated regulation of collagen gene expression. Types I and I11 are interstitial collagens which contribute about one-third each to the total hepatic collagen content. Type I corresponds to large collagen fibrills, while Type I11 forms fine fibrils. Basement membrane Type IV collagen is localized in the space of Disse and constitutes about 10% of the hepatic collagen. Type V is a pericellular collagen which contributes about 10% of the hepatic collagen. Collagen Type VI was recently detected in hepatic tissue of normal and CC1,-treated rats (Martinez-Hernandez, A. personal communication); its abundance and function are unknown.
Although increased production of collagen is indispen-Therapeutic Strategies for Hepatic Fibrosis 176 D. A. Brenner is a Pew Scholar in the Biomedical Sciences, and M. Chojkier is the recipient of a Career Research Development Award, Veterans Administration. GLOSSARY-antisense RNA: RNA that is complementary to the normally transcribed messenger RNA and is used to block the translation of messenger RNA into proteins; complementary DNA (cDNA): singie-stranded DNA complementary to a messenger RNA (i.e., the nucleotide bases of the cDNA and RNA will pair to form a duplex) and synthesized from it by in vitro reverse transcription; interkukin-1 (IL-1): a protein secreted by macrophage and other cells that has multiple effects, including cell proliferation, chemoattraction and induction of fever; phorbol esters: synthetic tumor-promoting compounds that activate protein kinase C; platelet-derived growth factor (FDGF): a protein produced by platelets and other cells that is a chemoattractant and stimulus for proliferation of mesenchymal cells; transforming growth factor @ (TGFb): a protein produced by platelets and other cells that modulates ceB development and the composition of the extracellular matrix; tumor necrosis factor alcachexin (TNFa): a protein synthesized by macrophage and other cells that has activities similar to interleukin-1 as well as inducing cachexia and cytotoxicity.