| First Author | De Franceschi L | Year | 2008 |
| Journal | FASEB J | Volume | 22 |
| Issue | 6 | Pages | 1849-60 |
| PubMed ID | 18245171 | Mgi Jnum | J:136578 |
| Mgi Id | MGI:3796503 | Doi | 10.1096/fj.07-098921 |
| Citation | De Franceschi L, et al. (2008) Protective effects of phosphodiesterase-4 (PDE-4) inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice. FASEB J 22(6):1849-60 |
| abstractText | 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. |
