Key result
The PDE-4 inhibitor rolipram prevented hypoxia-induced PDE-4 and -1 gene up-regulation and interfered with the development of pulmonary arterial hypertension in transgenic sickle cell mice.
Why the study?
Does the PDE-4 inhibitor rolipram prevent the development of pulmonary arterial hypertension in transgenic sickle cell mice exposed to hypoxia?
Does the PDE-4 inhibitor rolipram prevent the development of pulmonary arterial hypertension in transgenic sickle cell mice exposed to hypoxia?
PDE-4 inhibition with rolipram prevents the early phase of pulmonary arterial hypertension and modulates inflammatory factors in a sickle cell mouse model.
Supports PDE-4 inhibition in sickle cell PAH models; leaves open translation to human disease.
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 ) in creased neutrophil count in both bronchoalveoal lavage (BAL) and peripheral circulation; 2 ) increased BAL IL1β, IL10, IL6, and TNF‐α; and 3 ) up‐regulation of the genes; endothelin‐1, cyclo‐oxygenase‐2, angiotensin converting‐enzyme, and IL‐1β, suggesting that ampli fied inflammatory response and activation of the endo‐ thelin‐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 inter fered with the development of PAH, most likely through modulation of both vascular tone and inflam matory factors. This finding supports a possible thera peutic use of PDEs inhibitors in the earlier phases of PAH in SCD.— De Franceschi, L., Platt, O. S., Malpeli, G., Janin, A., Scarpa, A., Leboeuf, C., Beuzard, Y., Payen, E., Brugnara, C. Protective effects of PDE‐4 inhibition in the early phase of pulmonary arterial hypertension in transgenic sickle cell mice. FASEB J. 22, 1849–1860 (2008)
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Franceschi et al. (2008) studied Pulmonary arterial hypertension in sickle cell disease. Rolipram (PDE-4 inhibitor) vs. Hypoxia without rolipram was evaluated on Development of PAH and PDE-4/1 gene up-regulation. The PDE-4 inhibitor rolipram prevented hypoxia-induced PDE-4 and -1 gene up-regulation and interfered with the development of pulmonary arterial hypertension in transgenic sickle cell mice.
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