Anti-inflammatory and anti-fibrotic effects of the broad spectrum PDE inhibitor Pentoxifylline have suggested an important role for cyclic nucleotides in the pathogenesis of hepatic fibrosis; however studies examining the role of specific PDEs are lacking. Endotoxemia and Toll-like receptor 4 (TLR4) mediated inflammatory and pro-fibrotic signaling play a major role in the development of hepatic fibrosis. Since cAMPspecific PDE4 critically regulates LPS-TLR4 induced inflammatory cytokine expression, its pathogenic role in bile duct ligation induced hepatic injury and fibrogenesis in Sprague Dawley rats was examined. Initiation of cholestatic liver injury and fibrosis was accompanied by a significant induction of PDE4A, B and D expression and activity. Treatment with the PDE4-specific inhibitor, rolipram, significantly decreased liver PDE4 activity, hepatic inflammatory and pro-fibrotic cytokine expression, injury and fibrosis. At the cellular level, in relevance to endotoxemia and inflammatory cytokine production, PDE4B was observed to play a major regulatory role in the LPS-inducible TNF production by isolated Kupffer cells. Moreover, PDE4 expression was also involved in the in vitro activation and transdifferentiation of isolated hepatic stellate cells (HSCs). Particularly, PDE4A, B and D up-regulation preceded induction of the HSC activation marker α-SMA. In vitro treatment of HSCs with rolipram effectively attenuated α-SMA, collagen expression and accompanying morphological changes. Overall, these data strongly suggest that up-regulation of PDE4 expression during cholestatic liver injury plays a potential pathogenic role in the development of inflammation, injury and fibrosis.
- The American Society for Pharmacology and Experimental Therapeutics