Protective effects of phosphodiesterase-4 (PDE-4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice.
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.
De Franceschi
Lucia
L
Department of Clinical and Experimental Medicine, Section of Internal Medicine, University of Verona, Policlinico GB Rossi, 37134 Verona, Italy. lucia.defranceschi@univr.it
Platt
Orah S
OS
Malpeli
Giorgio
G
Janin
Anne
A
Scarpa
Aldo
A
Leboeuf
Christophe
C
Beuzard
Yves
Y
Payen
Emmanuel
E
Brugnara
Carlo
C
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
D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D020889:Rolipram