title: Protective effects of phosphodiesterase-4 (PDE-4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice.
abstract: Pulmonary arterial hypertension (PAH) is one of the leading causes of morbidity and mortality in adult patients with sickle cell disease (SCD). Here, we developed a model to study the early stage of PAH in SCD. We exposed wild-type and transgenic sickle cell SAD (Hbb(s)/Hbb(s)) mice to hypoxia (8% O(2)) for 7 days. Prolonged hypoxia in SAD mice only induced 1) increased neutrophil count in both bronchoalveolar lavage (BAL) and peripheral circulation; 2) increased BAL IL1beta, IL10, IL6, and TNF-alpha; and 3) up-regulation of the genes endothelin-1, cyclo-oxygenase-2, angiotensin-converting-enzyme, and IL-1beta, suggesting that amplified inflammatory response and activation of the endothelin-1 system may contribute to the early phase of PAH in SCD. Since phosphodiesterases (PDEs) are involved in pulmonary vascular tone regulation, we evaluated gene expression of phosphodiesterase-4 (PDE-4) isoforms and of PDE-1, -2, -3, -7, -8, which are the main cyclic-adenosine-monophosphate hydrolyzing enzymes. In SAD mouse lungs, prolonged hypoxia significantly increased PDE-4 and -1 gene expressions. The PDE-4 inhibitor, rolipram, prevented the hypoxia-induced PDE-4 and -1 gene up-regulation and interfered with the development of PAH, most likely through modulation of both vascular tone and inflammatory factors. This finding supports a possible therapeutic use of PDEs inhibitors in the earlier phases of PAH in SCD.
authors.affiliation: Department of Clinical and Experimental Medicine, Section of Internal Medicine, University of Verona, Policlinico GB Rossi, 37134 Verona, Italy. lucia.defranceschi@univr.it
authors.forename: Lucia
authors.initials: L
authors.lastname: De Franceschi
authors.forename: Orah S
authors.initials: OS
authors.lastname: Platt
authors.forename: Giorgio
authors.initials: G
authors.lastname: Malpeli
authors.forename: Anne
authors.initials: A
authors.lastname: Janin
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.forename: Christophe
authors.initials: C
authors.lastname: Leboeuf
authors.forename: Yves
authors.initials: Y
authors.lastname: Beuzard
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Payen
authors.forename: Carlo
authors.initials: C
authors.lastname: Brugnara
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications* / Q000188:drug therapy; D000818:Animals; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D000860:Hypoxia; D051379:Mice; D008822:Mice, Transgenic; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020889:Rolipram / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D020889:Rolipram