The major objectives of the present proposal are to determine how the homeostatic system of the normal liver is altered during the development of fibrosis in murine schistosomiasis and how this alteration is modified when the clay pipestem fibrosis is modulated. This modulation of liver pathology is a unique feature of schistosomiasis, and occurs in both the mouse model as well as in the human disease. In this regard, modulation of hepatic fibrosis in murine schistosomiasis occurs as the disease progresses from acute to chronic stages. As shown by previous studies in this laboratory, modulation of fibrosis is characterized by decreased hepatic granuloma size, a reduction in portal hypertension and a switch in the predominate type of collagen which comprises the hepatic fibrosis. Studies from this laboratory have also shown that modulation of fibrosis can occur in acute schistosomiasis infection with the passive transfer of specific serum components of chronic infection. In addition, changes in fibrosis can occur on parasitological cure with chemotherapy treatment. Therefore three differing methodologies (natural infection, immunomodulation and chemotherapy) can be utilized to study the modulation of fibrosis. The present proposal details the use of these three approaches and employs state-of-the-art molecular techniques to study in detail the components of the extracellular matrix as well as the fibrogenic cytokines responsible for the development of hepatic fibrosis. The techniques employed will include in situ hybridization, Northern blot and nuclear run-on assays as well as HPLC analysis. Noting that Schistosomiasis is probably the most common world-wide form of liver fibrosis, generation of data leading to the understanding of modulation of hepatic fibrosis may yield clinically relevant information of substantial significance. In addition, accomplishment of the specific aims of the present proposal would formulate a general model for the modulation of hepatic fibrosis and thereby aid in the formation of rational therapeutic intervention.
