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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI029102-01
Application #
3143795
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1990-01-01
Project End
1993-12-31
Budget Start
1990-01-01
Budget End
1990-12-31
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Miriam Hospital
Department
Type
DUNS #
039318308
City
Providence
State
RI
Country
United States
Zip Code
02906
Kresina, T F; Wisnewski, A; Love-Homan, L et al. (1994) Induction of hepatic pathology in SCID-Hu mice engrafted with peripheral blood lymphocytes of patients with Schistosomiasis japonica. J Infect Dis 170:733-6
Kresina, T F; He, Q; Degli Esposti, S et al. (1994) Gene expression of transforming growth factor beta 1 and extracellular matrix proteins in murine Schistosoma mansoni infection. Gastroenterology 107:773-80
Kresina, T F; He, Q; Degli Esposti, S et al. (1993) Hepatic fibrosis and gene expression changes induced by praziquantel treatment during immune modulation of Schistosoma japonicum infection. Parasitology 107 ( Pt 4):397-404
Annoni, G; Weiner, F R; Zern, M A (1992) Increased transforming growth factor-beta 1 gene expression in human liver disease. J Hepatol 14:259-64
Kresina, T F (1991) In vivo regulation of S. japonica granuloma formation by an IL-2 antagonist. Parasitology 102 Pt 2:243-9
Sun, M A; Wang, B E; Annoni, G et al. (1990) Two rat models of hepatic fibrosis. A morphologic and molecular comparison. Lab Invest 63:467-75