F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells: a link with liver fibrosis?
Carbon tetrachloride (CCl4)-induced hepatic fibrosis has been considered to be linked to oxidative stress and mediated by aldehydic lipid peroxidation products. In the present study, we investigated whether collagen synthesis is induced by F2-isoprostanes, the most proximal products of lipid peroxidation and known mediators of important biological effects. By contrast with aldehydes, F2-isoprostanes act through receptors able to elicit definite signal transduction pathways. In a rat model of CCl4-induced hepatic fibrosis, plasma F2-isoprostanes were markedly elevated for the entire experimental period; hepatic collagen content also increased. When hepatic stellate cells (HSCs) from normal liver were cultured with F2-isoprostanes in the concentration range found in the in vivo studies (10(-9)-10(-8) M), a striking increase in DNA synthesis (reversed by the thromboxane A2 antagonist SQ 29 548), in cell proliferation and in collagen synthesis was observed. Total collagen content was similarly increased. Moreover, F2-isoprostanes markedly increased the production of transforming growth factor-beta1 by U937 cells, considered a model of liver macrophages. The data provide evidence for the possibility that F2-isoprostanes generated by lipid peroxidation in hepatocytes mediate HSC proliferation and collagen production seen in hepatic fibrosis.
Comporti
Mario
M
Department of Pathophysiology, Experimental Medicine and Public Health, University of Siena, Siena, Italy. comporti@unisi.it
Arezzini
Beatrice
B
Signorini
Cinzia
C
Sgherri
Cristiana
C
Monaco
Barbara
B
Gardi
Concetta
C
D000818:Animals; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000032:analysis / Q000096:biosynthesis*; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D028441:F2-Isoprostanes / Q000097:blood / Q000494:pharmacology*; D005355:Fibrosis / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D007274:Injections, Intraperitoneal; D008099:Liver / Q000166:cytology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced* / Q000473:pathology*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D020298:U937 Cells
D028441:F2-Isoprostanes; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen; D004247:DNA; D002251:Carbon Tetrachloride