الفهرس 
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Abstract
Autoimmune hepatitis (AIH) is an inflammatory liver disease characterized histologically by interface hepatitis, biochemically by elevated transaminase levels and serologically by the presence of autoantibodies and increased levels of immunoglobulin G (IgG).
Recent studies have shown that exposure to silica can induce cyto-toxicity and oxidative stress in hepatocytes and lead to liver injury and fibrogenesis. The toxicity and tissue damage generated by silica in the body involve the production of ROS and nitric oxide.
Toll-like receptor (TLR) 4 is a member of the Toll-like receptor (TLRs) family. TLRs are a class of proteins that play a fundamental role in in innate immunity and inflammation. Increased TLR4 expression in liver tissue and activation of the TLR4 signal pathway initiates a cascade of events, including translocation of nuclear factor kappa B (NF-kB) p65 to the nucleus, leading to more production and release of hepatotoxic cytokines (TNF-α, INF- γ, IL-1b, IL-6, IL-12 and IL-18) which contribute to the development of hepatocyte damage through TLRs signal pathway. Also, TLR4 activation leads to hepatic fibrosis.
Interleukin-2 (IL-2) and tumour necrosis factor α (TNF-α) are potent inflammatory cytokines secreted in AIH and play an important role in the early development of inflammation and hepatocyte damage. IL-2 is a potent T cell growth factor, which can potently induce T cell expansion in vitro and in vivo. IL-2 is critical for the development and peripheral expansion of CD4+CD25+ regulatory T cells, which promote self-tolerance by suppressing T cell responses in vivo.
TNF-α is secreted by hepatic Kupffer cells and activated T cells and act as major mediator to initiate, amplify and promote the inflammatory response in hepatitis. TNF-α also induces other cytokines and chemokines that can recruit and induce cytotoxicity of lymphocytes, macrophages and neutrophils. Furthermore, TNF-α can induce hepatic cell apoptosis or necrosis via binding to TNF-α receptors.
Cyclosporine (CsA) is a calcineurin inhibitor derived from the fungal species Trichoderma polysporum. Cyclosporine (CsA) has potent lymphocyte specific immunosuppressive properties that primarily affect the T cell immune response by impairing NF-κB pathway and thereby, blocking production of IL-2, IL-3, IL-4, TNF-α, IFN- γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF). These genes and their translational products are critical for the generation of T cell immune response.
The goal of this study was to show the effect of Cyclosporine on altered hepatic function associated with silica-induced autoimmune hepatitis in rats and to reveal its effect on expression of toll-like receptor- 4 and interleukin- 2 in liver tissue.
In our study rats were divided into four groups control group was given normal saline of 0.9% NaCl orally once weekly for twelve weeks of the experiment, Silica-AIH group as autoimmune hepatitis was induced by a single dose of 3 mg of sodium silicate given orally once weekly for twelve weeks, Cyclosporine- treated group in which a single dose of 3 mg of sodium silicate was given orally once weekly for twelve weeks and after the eighth week, cyclosporine was given orally daily for four weeks at a dose of 2 mg/kg/day and Cyclosporine-prophylactic group in which cyclosporine was given orally daily at a dose of 2 mg/kg/day before sodium silicate and then sodium silicate was given once weekly orally for twelve weeks.
In all groups, serum level of ALT and AST were measured. Liver tissue sections were stained by H&E to examine histopathological changes. Also, the liver tissue was analyzed for IL-2 gene expression and TLR-4 gene expression using Real Time RT- PCR. Finally, the expression of TNF- α in liver tissues was examined by immunohistochemical staining.
Our results showed that silica- induced autoimmune hepatitis resulted in marked elevation of the serum levels of ALT and AST and severe piecemeal necrosis or interface hepatitis in liver biopsy. Cyclosporine could reduce their levels in a significant manner in addition to improving the histological alterations.
Autoimmune hepatitis was associated with up regulation of IL-2 and TLR-4 gene expression by real time RT-PCR in liver while cyclosporine significantly down-regulated their expression levels in liver tissue.
Additionally, immuno-histochemical staining for TNF- α in liver sections mostly increased in silica-AIH group (score 4) but it was obviously decreased in cyclosporine- treated group (score 2) and in prophylactic group (score 1).
Our results suggest that cyclosporine as calcineurin inhibitor may have a convincing therapeutic potentials in treating patients with immune-mediated hepatic diseases as it improved the histological alterations in liver and inhibited the production of proinflammatory cytokines, such as TNF-α together with reducing ALT and AST levels and gene expression of hepatic TLR-4 and IL-2.