Schistosoma mansoni: relationship of tumor necrosis factor-alpha to morbidity and collagen deposition in chronic experimental infection.

Chronic (20-week) Schistosoma mansoni infections in male CBA/J mice present as one of two pathophysiologic forms: severe hypersplenomegaly syndrome (HSS) or a less severe, moderate splenomegaly syndrome (MSS). HSS mice are cachectic (including anemia and hypertriglyceridemia) and exhibit high levels of periportal and perioval fibrosis. Because tumor necrosis factor-alpha (TNF-alpha) is associated with the symptoms of cachexia, we measured TNF-alpha protein and mRNA levels in the livers of infected and uninfected animals. TNF-alpha levels in liver homogenates from mice with acute infections (8-week) were high (mean +/- SEM; 41.0 +/- 1.6 ng/g tissue) and remained high in livers of HSS mice (41.8 +/- 3.0 ng/g tissue) while TNF-alpha levels in liver homogenates of MSS mice were significantly lower (27.9 +/- 2.0 ng/g tissue). Similarly, hepatic TNF-alpha mRNA levels from HSS mice were two- to threefold higher than those from MSS mice. Hydroxyproline levels in these animals were determined as a measure of collagen deposition and fibrosis and showed increased overall levels in the livers of HSS animals. To investigate the progression of HSS development, hematocrit and serum triglyceride levels were followed over a 20-week period after infection. In mice that developed HSS, hematocrit levels decreased significantly and progressively from Weeks 10 through 20. These same animals showed significant increases in serum triglycerides compared to 8-week-infected mice or the mice which developed MSS over the same time period. These results suggest that failure to downregulate hepatic production of TNF-alpha correlates with, and may contribute to, the development of liver fibrosis and HSS in experimental schistosomiasis.