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  • Title: The pharmacological approach to reverse portal hypertention and hepatic schistosomal fibrosis in Egypt, control experimental study.
    Author: Helmy AH, Abdel-Hady AA, el-Shanawany F, Hammam O, Abdel-Hady A.
    Journal: J Egypt Soc Parasitol; 2005 Dec; 35(3):731-50. PubMed ID: 16333884.
    Abstract:
    Schistosoma mansoni is the most prevalent cause of liver fibrosis in Egypt. It is characterized by hepatocyte damage, inflammation and chronic parasite egg-induced granuloma formation leading to fibrosis. Its management, particularly fibrosis, has focused primarily on treating and preventing the complications of portal hypertension. Unfortunately, there is no therapy that has been proved to prevent progressive hepatic fibrosis which is associated with a significant morbidity and mortality due to granulomatous hypersensitivity to parasite eggs. However, recent developments in understanding hepatic fibrogenesis confirm that recovery from advanced fibrosis is possible. There is a considerable imperative to develop anti-fibrotic strategies that are applicable to liver fibrosis. It was noted that a marked increase in the amount of different interstitial collagens types are associated with the development of fibrotic liver diseases. Meanwhile, it has been suggested that as long as the relative portions of liver collagen are still within the normal limits, the fibrosis may still be reversible. If it exceeds the normal limits fibrogenesis will proceed to its end stage, even if the etiological agent is removed. Collagen type IV and procollagen type III are two of the most accurate fibrosis markers which allow reliable non-invasive diagnosis. The T lymphocytes and the immuno-regulatory cytokines may be important in the host response to S. mansoni granuloma formation and fibrosis. Chronic parasite egg-induced granuloma formation can lead to fibrosis, which is immunologically characterized by the dominant Th2 response. Corticosteroids and prostaglandins interfere with both efferent and afferent mechanisms of immune function. These data indicate that this adjuvant therapy can be a candidate for therapeutic intervention in hepatic fibrosis through induction of a balance between Th1 and Th2 cells response as will be documented by the fibrosis markers. One hundred S. mansoni infected hamsters (150-250 gm) were obtained from the BRPU-TBRI (5 groups, 20 hamsters each). Treatment was started 10 weeks post infection. First G (20 hamsters) was neither infected nor treated, second G. was infected but untreated, third group infected and PZQ treated, forth G. infected and PZQ and MP treated and fifth group infected and PZQ and PgE1 treated. Samples (liver and blood) were obtained 20 weeks post infection. The serum level of: liver functions, procollagen type III, collagen type IV & Th1 cytokine (IL-2) and Th2 cytokine (IL-10) were performed. Histopathology was performed to study liver fibrosis, measuring the proliferate activity of the hepatocytes using cell image analyzer system and granuloma cells using the indirect immuno-histochemistry by monoclonal antibody proliferating cell nuclear antigen (PCNA). In this study, G.V showed high significant reduction in granuloma size, type and percentage of fibrosis and significant elevation in percentage of degenerated ova compared to Gs.III & IV. The proliferation index measured using PCNA showed high proliferative activity of hepatocytes in non treated group which declined in the treated Gs.III, IV & V. The proliferation activity of hepatocytes and granuloma forming cells decreased significantly in G.V compared to G.IV. There was a significant reduction in liver function tests even tendency for normalization in G.V compared to group III and IV. Procollagen type III and collagen type IV were significantly low in the serum in G.V compared to Gs.III & IV. Th1 (IL-2) level was significantly high in G.V compared to Gs.III, IV and Th2 (IL-10) was significantly low in G.V compared to Gs III & IV indicating the low amount of fibrosis was in the group treated with PZQ PgE1.PgE1 with PZQ to treat S. mansoni infected hamsters can modulate liver fibrosis and improves the liver function tests up to normalization. The balance between Th1 and Th2 cytokines level could be modulated to help reverse or decrease fibrosis in S. mansoni infected hamsters. This may pave the way for clinical application as combined therapy PZQ and PgE1 may by an effective approach to reverse hepatic fibrosis in schistosomiasis by the induction of dominant Th1 response.
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