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Liver plasma membrane-associated fibroblast growth: stimulatory and inhibitory activities during experimental
N D Belyaev1, V G Budker, L V Deriy
1Institute of Bioorganic Chemistry, Siberian Division of the USSR Academy of Sciences, Novosibirsk.
Abstract:
During experimental CCl4 cirrhosis, an increase of membrane-associated factor stimulating 3T3 cell proliferation in vitro was observed. This stimulator is a 150-kD protein similar to one previously described. In situ perfusion released growth stimulatory activity, suggesting a peripheral plasma membrane protein localizing on basolateral surfaces. The activity increased with increasing number of CCl4 treatments, reaching a maximum at the 14th intoxication. It was faster than the proliferation of connective tissues determined histologically. Cessation of treatment caused a decrease in activity to that of the level of untreated liver, although the number of fibroblastlike cells remained large. This data, taken with the results of experiments with enriched hepatocyte fraction, may serve as an evidence in favor of hepatocyte origin of the factor. A factor inhibiting fibroblast proliferation was measured in detergent extracts from membranes, suggesting an integral membrane protein. The activity of the inhibitory factor increased in acute liver lesions, but at the stage of maximal fibrogenesis this factor is reduced to levels comparable to those of the intact liver. Therefore it is unlikely that this factor is involved in CCl4-induced fibrogenesis at the final stages. These factors may be common controls for various hepatic lesions causing fibrosis, both in clinical and experimental modeling.
Insights
Researchers identified a liver cell growth stimulator and a fibroblast inhibitor during carbon tetrachloride (CCl4) induced cirrhosis. These factors may regulate liver fibrosis in various hepatic lesions.
Area of Science:
- Hepatology and cell biology
- Biochemistry of liver injury
Background:
- Carbon tetrachloride (CCl4) intoxication is a common model for inducing experimental liver cirrhosis.
- Liver fibrosis involves complex cellular and molecular mechanisms, including the roles of growth factors and inhibitors.
Purpose of the Study:
- To investigate membrane-associated factors influencing cell proliferation and fibroblast activity during experimental CCl4-induced liver cirrhosis.
- To determine the origin and dynamics of these factors in relation to fibrogenesis.
Main Methods:
- Experimental induction of cirrhosis in rats using CCl4.
- In situ liver perfusion to assess growth stimulatory activity.
- Analysis of membrane extracts for inhibitory factors.
- Histological assessment of connective tissue proliferation.
- Experiments with enriched hepatocyte fractions.
Main Results:
- A 150-kD membrane-associated protein stimulating 3T3 cell proliferation was identified, with activity peaking after 14 CCl4 treatments.
- This stimulatory activity, originating from hepatocytes, increased faster than histological fibrosis.
- A membrane-bound factor inhibiting fibroblast proliferation was found, elevated in acute lesions but reduced during maximal fibrogenesis.
- Cessation of CCl4 treatment decreased stimulatory activity to baseline levels despite persistent fibroblast numbers.
Conclusions:
- Hepatocytes likely produce a growth factor that increases during CCl4-induced cirrhosis.
- An inhibitory factor's reduced activity during late-stage fibrogenesis suggests it's not a primary driver of CCl4-induced fibrosis.
- These identified factors may play a role in regulating fibrosis across different types of liver injury.