SCHISTOSOMA-MANSONI - RELATIONSHIP OF TUMOR-NECROSIS-FACTOR-ALPHA TO MORBIDITY AND COLLAGEN DEPOSITION IN CHRONIC EXPERIMENTAL-INFECTION

Relationship of tumor necrosis factor-alpha to morbidity and collagen deposition in chronic experimental infection. Experimental Parasitolog y 84, 115-123. Chronic (20-week) Schistosoma mansoni infections in mal e CBA/J mice present as one of two pathophysiologic forms: severe hype rsplenomegaly syndrome (HSS) or a less severe, moderate splenomegaly s yndrome (MSS). HSS mice are cachectic (including anemia and hypertrigl yceridemia) and exhibit high levels of periportal and perioval fibrosi s. Because tumor necrosis factor-alpha (TNF-alpha) is associated with the symptoms of cachexia, we measured TNF-alpha protein and mRNA level s in the Livers of infected and uninfected animals. TNF-alpha levels i n 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 t issue). Similarly, hepatic TNF-alpha mRNA levels from HSS mice were tw o- 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 aft er infection. In mice that developed HSS, hematocrit levels decreased significantly and progressively from Weeks 10 through 20. These same a nimals showed significant increases in serum triglycerides compared to 8-week-infected mice or the mice which developed MSS over the same ti me period. These results suggest that failure to downregulate hepatic production of TNF-alpha correlates with, and may contribute to, the de velopment of liver fibrosis and HSS in experimental schistosomiasis.