Thesis (Ph.D.) - Cairo University - Faculty of Veterinary Medicine - Department of Clinical Pathology

The activation of cannabinoid receptor 2 (CB2) plays a pleiotropic role in the innate immunity and is considered a crucial mediator in liver and lung disease. This study aimed to explore the role of activating CB2 using synthetic agonist (AM1241) on suppressing the progress of liver fibrosis induced by two models; bile duct ligation (BDL) and TAA administration as well as lung fibrosis induced by bleomycin (BLM) instillation. The study also attempted to clarify the mechanisms of the antifibrotic effects of synthetic CB2 agonists; AM1241 on the ongoing both hepatic and pulmonary fibrosis. AM1241 was administrated to rats of the aforementioned three models in two doses (3 and 6 mg/kg) for 14 days (in BDL experiment) and 21days (for the other experiments). Liver function and oxidative stress markers, hepatic TNF-Ü, IL-6 and IL-10, IL-1Ý, TGF-Ý1, RT-qPCR expression of Toll like receptor 4 (TLR4), TGF-Ý1, Ü-SMA and microRNA- 155 (miR-155) genes, western blot for Vimentin and E-cadherin proteins, immunohistochemical expression of CD31, CD34, Ü-SMA and NF-mB as well as histopathology of liver tissue were all assessed. In lung experiment, miRNA-21, Myd88 and TLR4 genes expression were detected by RT-q-PCR, while collagen I, Smad2 and Myd88 protein levels were analyzed by western blot. In addition, antioxidant activity (SOD and GSH), pro-fibrotic (TGF-Ý1) and pro-inflammatory (IL- 4 and IL-13) cytokines were determined in lung tissue homogenate using ELISA kits. Histological examination and immunohistochemical (IHC) evaluation of CD4, Ü-SMA and TGF- Ý1 expression were also examined. In both liver models; AM1241 administration at both doses significantly (P<0.05) ameliorated liver function markers, pro-inflammatory cytokines (TNF-Ü, IL-6), significantly decreased i GSH content and TLR4 gene expression

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