It is well known that chronic biliary inflammation is a risk factor for biliary carcinogenesis. However, the molecular mechanisms of biliary carcinogenesis as a consequence of chronic biliary inflammation remain unclear.
Inducible nitric oxide synthase (iNOS) is induced in inflamed tissues and generates large amounts of nitric oxide (NO) that can promote mutagenic changes in DNA through DNA oxidization and protein nitrosylation.
In a research article to be published on December 21 in the World Journal of Gastroenterology, Dr. Kitasato and colleagues investigated the role of iNOS activation, NO generation, and DNA damage as the link between chronic inflammation and biliary carcinogenesis, utilizing normal hamster gallbladder epithelial cells cultured in the presence of inflammatory cytokines.
NO generation was increased significantly following cytokine stimulation. Furthermore, the production of NO in the presence of inflammatory cytokines was completely suppressed by the addition of an iNOS inhibitor. The expression of iNOS mRNA in the gallbladder epithelial cells was clearly demonstrated in the presence of cytokine-stimulation, compared with that in the absence of stimulatory cytokines. Moreover, NO-dependent DNA damage was increased significantly by cytokines, and decreased to control levels by an iNOS inhibitor.
In this study, the researchers used primary epithelial cells isolated from hamster gallbladders. These normal epithelial cells are suitable for estimating the involvement of iNOS and NO in biliary carcinogenesis, especially in the initiation of biliary carcinoma as a response to chronic inflammation.
In normal hamster gallbladder epithelial cells, cytokine stimulation induced iNOS expression and NO generation, which was sufficient to cause DNA damage. The results of this study suggest that NO-mediated genotoxicity induced by inflammatory cytokines through activation of iNOS is involved in the process of biliary carcinogenesis in response to chronic inflammation of the biliary tree. These findings represent a new link between infection and carcinogenesis that may be applied broadly beyond the biliary tract.
|Contact: Jing Zhu|
World Journal of Gastroenterology