Dynamics of hepatic connective tissue matrix constituents during murine schistosoma mansoni infection

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Abstract
Hepatic fibrosis is the major clinical sequela of infection with the helminth Schistosoma mansoni. However, little is known regarding its dynamics and regulation in schistosomiasis. The present study presents the dynamics of deposition and resorption of two major extracellular matrix components of fibrosis, glycosaminoglycans and collagens, during the course of experimental S. mansoni infection. Early in infection (6 weeks), glycosaminoglycan biosynthesis was markedly elevated, as was collagen biosynthesis. This led to significant accumulations of these two molecules at a glycosaminoglycan/collagen ratio similar to that observed in livers of un-infected mice (uronic acid/hydroxyproline ratio of 1.10 at 6 weeks compared to normal value of 1.25). During maximal hepatic fibrosis (12 to 18 weeks), both collagen and glycosaminoglycan biosynthesis continued to increase but the extracellular matrix shifted to a lower glycosaminoglycan/collagen ratio of 0.42, suggesting enhanced glycosaminoglycan breakdown. In addition, during this acute stage of infection, Type I collagen was the predominant isotype synthesized, whereas total collagenolytic activity degrading Type I collagen was maximal. During chronic infection, a decrease in the content of both hepatic glycosaminoglycans and collagens were noted, with a glycosaminoglycan/collagen ratio of 0.63. Decreased glycosaminoglycan content paralleled diminished biosynthetic rates. On the other hand, an over 50% reduction in collagen content (from 18 to 24 weeks) appeared not to result from diminished biosynthesis but from a switch in the predominant collagen isotype synthesized (from Type I to Type III), matched by an enhanced constitutive collagenolytic activity directed toward this type of collagen. These differences in the extracellular matrix separate schistosomal-induced hepatic fibrosis from most other types of fibrotic liver disease and may explain differences in the clinical manifestations observed during different stages of infection.