Rolipram Attenuates Bile Duct Ligation–Induced Liver Injury in Rats: A Potential Pathogenic Role of PDE4

Abstract

Anti-inflammatory and antifibrotic effects of the broad spectrum phosphodiesterase (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 profibrotic signaling play a major role in the development of hepatic fibrosis. Because cAMP-specific PDE4 critically regulates lipopolysaccharide (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 profibrotic 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 tumor necrosis factor (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 upregulation preceded induction of the HSC activation marker a-smooth muscle actin (a-SMA). In vitro treatment of HSCs with rolipram effectively attenuated a-SMA, collagen expression, and accompanying morphologic changes. Overall, these data strongly suggest that upregulation of PDE4 expression during cholestatic liver injury plays a potential pathogenic role in the development of inflammation, injury, and fibrosis.

Inhibition of phosphodiesterase 4 (PDE4) reduces dermal fibrosis by interfering with the release of interleukin-6 from M2 macrophages

“…Gobejishvili et al 46 and Udalov et al 47 investigated PDE4 blockade in models of cholestatic liver disease and chronic lung injury, respectively, supporting the idea that PDE4 might play a general role in chronic organ damage. In detail, cholestatic liver injury induced by bile duct ligation was accompanied by increased PDE expression.…”

Misoprostol modulates cytokine expression through a cAMP pathway: Potential therapeutic implication for liver disease

“…Our earlier work documented that decreased cAMP levels played a causal role in the priming of monocytes/macrophages leading to an increase in LPS-inducible TNF expression [50]. We have also shown that increased cAMP signaling significantly attenuates liver inflammation, injury and development of fibrosis [59]. The results from the present study strongly indicate that Misoprostol both in vivo and in vitro is highly effective in decreasing the expression of the endotoxin-inducible pro-inflammatory cytokine, TNF, and increasing the anti-inflammatory cytokine, IL-10.…”

Medical Management of Severe Alcoholic Hepatitis: Expert Review from the Clinical Practice Updates Committee of the AGA Institute

“…Importantly, PDE4 inhibitors have also been demonstrated to upregulate the anti-inflammtory/antifibrotic cytokine IL-10 (31-35). Recent studies have shown a pathogenic role of PDE4 enzymes in the development of cholestatic liver injury/fibrosis, and significant protection using a PDE4-specific inhibitor (36). Experimental and clinical studies provide a rationale for targeting PDE4 as a therapeutic strategy for treatment of ALD, but this has been hampered by dose-associated side effects including severe nausea, emesis, and sedative effects caused by the increased cAMP levels in the central nervous system (25, 37).…”