The Potential Anti-fibrotic Effect of Theophylline and Celecoxcib in Concanavalin A Induced Immunological Liver Fibrosis in Rats

Abstract

Background and aim: Liver fibrosis and its end-stage sequela of cirrhosis are major causes of morbidity and mortality worldwide. Some drugs that are currently in use for other human diseases as theophylline may have antifibrotic effects in the lung by inhibiting lung fibroblast proliferation. Celecoxib has a proapoptotic effect on cancer cells and may be on hepatic stellate cells. It is thought that selective induction of HSC apoptosis would be a way to control liver fibrogenesis. This study aimed to investigate the effects of low dose of theophylline and celecoxib either alone or in combination on the biochemical and the histopathological changes of liver tissues as well as their effects on portal venous pressure in rats with immunological hepatic fibrosis. Methods: Immunological hepatic fibrosis model was induced by concanavalin A (Con A). The rats were randomly assigned to the normal vehicle control, Con A (20mg/kg/once weekly IVI), Con A + theophylline (20mg/kg/day), Con A + celecoxib (20mg/kg/day) and Con A + theophylline + celecoxib groups. The five groups were continuously given agents either for 4 weeks or 8 weeks (theophylline and celecoxib by gastric gavage). Results: There was a time dependent increase in the liver injury parameters by the end of the 4th and 8th weeks in the Con A treated group. Low dose of theophylline produced a significant decrease in serum alanine transaminase, aspartate transaminase, interferon gamma, hepatic transforming growth factor-beta and hydroxyproline content (except portal venous pressure) compared to celecoxib. Also, low dose of theophylline produced significant improvement in the histopathological and immunohistochemical results compared to celecoxib. Combination therapy of low dose theophylline and celecoxib produced a significant decrease in all parameters measured (except portal venous pressure) compared to low dose of theophylline alone. Conclusion: low dose theophylline and celecoxib administration significantly decreased the biochemical markers, portal venous pressure and improved the histopathological and immunohistochemical results in rats with immunological hepatic fibrosis. Low dose theophylline produced more significant decrease in all biochemical markers and improvement in the histopathological and immunohistochemical studies except portal venous pressure, there was insignificant decrease in comparison to celecoxib. While combination therapy of low dose theophylline and celecoxib may offer advantages over the use of low dose theophylline alone.

Key words: Concanavalin A; Theophylline; Celecoxib; hydroxyproline; transforming growth factor-beta; portal hypertension.