Themedical definition of cholestasis is a retaining bile excreted substances intothe bile itself again. There are causedby many different causes underly this condition including inherited andacquired pathologies. Inherited cholestasis is an autosomal recessive diseasewhile, the acquired cholestasis refers to bile secretion caused via severaldefects such as bile duct obstruction, hepatitis,biliary cirrhosis, cholangiocarcinoma or via hormonal disturbances duringpregnancy (Jungstand Lammert, 2013; Zollner and Trauner, 2008). Consequently, these conditionslead to bile acids accumulation in hepatic tissues causing a potential to hepatotoxicity(Guicciardiand Gores; Perez and Briz, 2009).
Pathophysiologically,obstructive cholestasis increases biliary pressure which leads to rupture in cholangiolesleading to bile reflux back into hepatic tissues causing hepatotoxicity (Fickertet al., 2002). Hepatotoxicity initiates inflammatory response via secretionof osteopontin and CXC chemokines by hepatocytes which in turn leading to an extensive neutrophil accumulation which induces liver injury (Gujralet al., 2003; Kim et al.
, 2006; Kountouras et al., 1984; Licata et al., 2013;O’Brien et al., 2013; Saito and Maher, 2000). Lithocholicacid (LCA) is one of these bile acidsthat essentially acts as a detergent for dietary fat solubilization andabsorption (Fisheret al., 1982; Hofmann, 2004).
LCA is a secondary bile acidformed by colon bacterial enzyme called 7 alpha-dehydroxylase (Reddyet al.). LCAis a hydrophobic compound implicated in several diseases such as colon cancer,hepatotoxicity and liver injury (Ajouzet al., 2014; Lucangioli et al., 2009).
Experimentally, LCA feeding wasused as a model of liver injury by Fickert et al. in which LCA precipitates inboth hepatic and biliary tissues causing obstructive cholestasis and initiatesinflammatory cycle (Fickertet al., 2002). On the other hand, Artemisinin is a chemical compound synthesized either naturally by a plantcalled Artemisia annua or artificially (Guo,2016). It is a sesquiterpene lactonecontaining a peroxide bridge which might be responsible for its action (Averyet al., 1993). BothArtemisinin and its derivatives have been reported to be effective treatmentfor several viral infections, toxoplasmosis and against Pnuemocystis carinii as well as these compounds have been shownto be effective against some human cancer cell lines (Efferth,2007; Efferth et al., 2008; Merali and Meshnick, 1991).
Furthermore, artemisinin have beenshown to be a good treatment for different parasitic diseases such as malaria, leishmaniosis,and African sleeping sickness (Mishinaet al., 2007; Posner et al., 1999; Sen et al., 2007; White, 1997). In the same context, artemisininhas also anti-inflammatory and immunomodulatory effect (Ferreiraet al.
, 2010). In terms of liver injury Chin Q etal have reported that dihydroartemisinin prevents liver fibrosis due to its actionon both apoptosis pathway and PDGF/MAPK pathway in experimental animals (Chenet al., 2016a; Chen et al., 2016b). Thus,the objective of this project is to study the effect of artemisinin on LCA- inducedliver injury in animal model on both cellular and molecular scales.