| Summary: | 博士 === 長庚大學 === 臨床醫學研究所 === 105 === Inherited syndromes of intrahepatic cholestasis and biliary atresia are the most common causes of cholestatic liver disease and the chief indication for liver transplantation in children. Cholestatic liver disease causes not only progressive end-stage liver disease but also extra-hepatic complications e.g. hepatic encephalopathy (HE) and hepatopulmonary syndrome. Patients with HE have increased mortality and poorer quality of life. Cholestasis is now recognized as a disorder of liver oxidant overload. Patients with liver cirrhosis were reported to have poor cognition and higher serum asymmetric dimethylarginine (ADMA). Circulating levels of TNF-α are not only increased in patients with chronic liver failure but also correlate significantly with the severity of HE. Rats subjected to bile duct ligation (BDL) exhibit increased systemic oxidative stress, increased circulating and hepatic ADMA levels and brain dysfunction characteristic of hepatic encephalopathy (HE).
Therefore, we explored the temporal progression of BDL induced cholestasis in developing rats, focusing on brain cognition and liver and kidney pathology. We found liver and renal outcome were worse in the BDL 4 weeks (BDL4) rats than in the (BDL 2 weeks) BDL2 rats. BDL4 rats also exhibited more severe spatial memory deficits than BDL2 rats. In the second part, we first determined the temporal profiles of TNF-α and ADMA in the plasma, brain cortex, and hippocampus in young BDL rats. Next, we examined whether etanercept was beneficial in preventing brain damage. We found increased plasma TNF-α and ADMA levels, increased cortical TNF-α mRNA and protein and ADMA, and hippocampal TNF-α mRNA and protein, and spatial defects in young BDL rats. Combined intraperitoneal (IP) and intrathecal (IT) etanercept administration reduced the increased cortical and hippocampal TNF-α mRNA and protein level as well as spatial deficits.
In the third part, we studied the potential protective activity of melatonin in young BDL rats. We found BDL group rats showed liver apoptosis, increased pro-inflamamtory mediators, caspases alterations, anti-apoptotic factors changes, and dysfunction of ER homeostasis. Melatonin effectively reversed apoptosis, mainly through intrinsic pathway and reversed ER stress.
Taken together, our findings highlighted similar progression of liver, kidney, and brain damage and the importance of ADMA and oxidative stress in the development of BDL induced organ damage in developing rats. Dually IP/IT etanercept administration reduced the increased cortical and hippocampal TNF-α mRNA and protein level as well as spatial deficits. Melatonin rescued the apoptotic changes of liver via the intrinsic pathway. Better understanding of the temporal progression of multiple organ damages encountered in developing rats with cholestasis and their possible mechanisms and treatments will provide us useful information regarding management of extrahepatic complications and timing decisions for liver transplantation in children with cholestasis.
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