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Granuloma collagenase and EDTA-sensitive neutral protease production in hepatic murine schistosomiasis
Abstract:
Mice infected with Schistosoma mansoni represent a model for study of hepatic fibrosis in humans. Production of trypsin-activatable inactive collagenase and EDTA-sensitive neutral protease was measured in the culture medium in which granuloma explants or primary cultures were maintained. Collagenase production was maximal in granulomas obtained from liver of mice 8 weeks postinfection and was inhibited by Actinomycin D or cycloheximide, and enhanced by lymphocyte factor(s) or heparin. Isolated schistosome eggs did not release these enzymatic activities but did release EDTA-insensitive protease activity. Both enzymes were separated by ion-exchange chromatography and purified to homogeneity. Isolated collagenase had an isoelectric point of 6.2 and molecular weight of 60,000 and had the functional characteristics of a tissue collagenase. The specific activity of collagenase was 33 units per mg protein at an optimum pH 7.5 and lacked proteolytic activity against noncollagenous protein substrates. Isolated EDTA-sensitive neutral protease had specific caseinolytic activity of 150 units per mg protein and gelatinolytic activity of 300 units per mg protein at an optimum pH 7.5; the enzyme lacked activity against undenatured collagen. Isoelectric point was pH 6.0. Protease activity was inhibited by known inhibitors of collagenases. Production and activation of EDTA-sensitive neutral protease and collagenase accompany increased collagen synthesis and content in the liver of mice 8 weeks postinfection with S. mansoni cercariae. Continued accumulation of liver collagen under these conditions suggests an insufficiency in collagenase activity relative to the increase in collagen synthesis.
Insights
Schistosoma mansoni infection in mice models human hepatic fibrosis. Researchers identified collagenase and neutral protease involved in liver fibrosis, noting an imbalance between collagen synthesis and degradation.
Area of Science:
- Biochemistry
- Immunology
- Parasitology
Background:
- Schistosoma mansoni infection in mice serves as a model for human hepatic fibrosis.
- Hepatic fibrosis involves complex enzymatic processes, including collagen synthesis and degradation.
Purpose of the Study:
- To investigate the production and characteristics of collagenase and neutral protease in Schistosoma mansoni-infected mouse liver granulomas.
- To understand the role of these enzymes in the development of hepatic fibrosis.
Main Methods:
- Culture of granuloma explants and primary cells from infected mouse livers.
- Measurement of enzymatic activities (collagenase, neutral protease) in culture supernatants.
- Purification of enzymes using ion-exchange chromatography.
- Characterization of purified enzymes (isoelectric point, molecular weight, substrate specificity).
Main Results:
- Collagenase production peaked at 8 weeks post-infection and was regulated by inhibitors and enhancers.
- An EDTA-sensitive neutral protease with gelatinolytic and caseinolytic activity was identified.
- Both enzymes were purified and characterized, showing distinct properties but sensitivity to collagenase inhibitors.
- Enzyme production correlated with increased collagen synthesis, but collagen accumulation suggested insufficient degradation.
Conclusions:
- The study identified and characterized key enzymes, collagenase and EDTA-sensitive neutral protease, involved in Schistosoma mansoni-induced hepatic fibrosis.
- An imbalance between collagen synthesis and degradation, potentially due to insufficient collagenase activity, contributes to progressive liver fibrosis.
