title: 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 α-smooth muscle actin (α-SMA). In vitro treatment of HSCs with rolipram effectively attenuated α-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.
authors.affiliation: Department of Internal Medicine (L.G., S.B., J.Z., D.V.A., C.J.M.) and Department of Pharmacology and Toxicology (S.B., D.V.A., C.J.M.), University of Louisville, Louisville, Kentucky; Department of Surgery, University of Louisville Medical Center, Louisville, Kentucky (Y.L.); VA Medical Center, Louisville, Kentucky (C.J.M.); University of Louisville Alcohol Research Center Louisville, Kentucky (L.G., S.B., J.Z., D.V.A., C.J.M.); and Department of Medicine II, Section Molecular Hepatology-Alcohol Associated Diseases, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (K.B.-H., S.D.).
authors.forename: Leila
authors.initials: L
authors.lastname: Gobejishvili
authors.forename: Shirish
authors.initials: S
authors.lastname: Barve
authors.forename: Katja
authors.initials: K
authors.lastname: Breitkopf-Heinlein
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: JingWen
authors.initials: J
authors.lastname: Zhang
authors.forename: Diana V
authors.initials: DV
authors.lastname: Avila
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D001649:Bile Duct Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000502:physiology*; D008026:Ligation; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000473:pathology*; D008297:Male; D058988:Phosphodiesterase 4 Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D020889:Rolipram / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C546993:PDE4B protein, rat; C528468:PDE4D protein, rat; C521385:Pde4a protein, rat; D020889:Rolipram