Dynamics of hepatic glycosaminoglycan accumulation in murine Schistosoma japonicum infection

Abstract

Hepatic fibrosis is the major pathologic sequela of schistosomiasis and is comprised of extracellular collagen and proteoglycan macromolecules. Glycosaminoglycans (GAGs), the major constituents of proteoglycan molecules, were studied in mice infected with Schistosoma japonicum. Total GAG content was measured by extraction of uronic acid from murine liver sections and isolated hepatic granulomas during the progression from acute (0–15 wk) to chronic (20–30 wk) infection. Infected livers contained elevated levels of uronic acid throughout infection when compared to noninfected livers. Glycosaminoglycan content was found to peak at a value of 2.5 ± 0.1 pmol/mg tissue (five times normal value) in acute infection (6–15 wk), a time of increasing hepatic fibrosis. Peak uronic acid content in isolated granulomas was also observed during acute infection with a maximal value of 7.1 ± 0.9 pmol/mg tissue (9–11 wk). During chronic infection (30 wk), hepatic uronic acid content was reduced by 68% in unfractionated liver tissue and by 49% in isolated granulomas (both p < 0.05). This modulation in GAG accumulation appeared to result from decreased biosynthesis, inasmuch as during chronic infection GAG biosynthetic rates fell by 42% in liver tissue and 53% in isolated granulomas (both p < 0.05). In addition to these quantitative changes in GAG metabolism, GAG disaccharides were examined qualitatively by high-pressure liquid chromatography, which resolved nonsulfated, 6-sulfated, and 4-sulfated disaccharides. Few qualitative changes were seen in the GAG profile between normal liver and acutely or chronically infected liver. Both the rapid modulation of GAG accumulation despite ongoing infection and its qualitative makeup differentiate hepatic fibrosis seen in schistosomiasis japonica from that observed in many other forms of fibrotic liver disease.