The Changes Of Phosphodiesterase-4 Activity In The Rat Model Of Acute Lung Injury And The Effect Of PDE4 Inhibitor

Cyclic nucleotide phosphodiesterases-4 (PDE4) provide the only route for degrading cyclic AMP (cAMP), a key second messenger inside cells, thus providing a pivotal means of regulating cAMP levels. Their importance is emphasized by the multiplicity of cAMP-hydrolyzing PDEs. Of these, the multi-gene PDE4 family has attracted considerable attention over the past decade because PDE4-selective inhibitors have potential therapeutic use in a range of major disease areas. Inhibitors of PDE4 are efficacious for ALI in animal models and have shown some efficacy in human ALI. Regulation of PDE4 in ALI has been widely investigated in blood leukocytes with discrepant results. In this study, we investigated the PDE4 activity, the relationship between the inflammation and PDE4 activity in the lungs in rat models of ALI, and potential interventions of PDE4 inhibitors and antiinflammatory drugs in the reduction of lung inflammation and goblet cell hyperplasia in ALI rats. The main contents are divided into some sections as follows:1. Lung tissues PDE4 activity significantly increased as early as 1 h, peaked 6 h, and then markedly lowered at 24 h after intratracheal administration of LPS2. Total white cell and neutrophil in bronchoalvelar lavegar fluid significantly increased as early as 1 h, peaked 6 h, and then markedly lowered at 24 h after intratracheal administration of LPS3. TNF-a level in lung tissue rapidly peaked 2 h and lowered 24 h after intratracheal administration of LPS;4. The change of PDE4 activity accorded with the change of total white cell and neutrophil in the BALF (r =0.83, PO.05);5. The LPS-induced increase in neutrophils and lung oedema, MPO and 02*" activity in BAL was significantly reduced by piclamilast pretreatment(P<0.01)6. The LPS-induced increase in TNF-a release in the lung was significantly reduced by piclamilast pretreatment (PO.05~0.01). In contrast, IL-10 level in the lung was decreased by LPS but restored by piclamilast but was not depended on dosage.7. The change of PDE4 activity accorded with the ratio of TNF-a / IL-10, DXM 1 mg ? kg"1 also can reduce the TNF-a and restore the IL-10 level decreased by LPS, however it could not reduce the PDE4 activity in the rat lung in ALL8. The large of neutrophil recruit and albumen extravasate in lung tissues when 6 h after LPS-induced, it can be improved by piclamilast pretreatmentConclusionOur data suggest, for the first time, that PDE4 enzyme activity in the lung was significantly increased by the LPS. Lung tissues PDE4 activity significantly increased as early as 1 h, peaked 6 h, and then markedly lowered at 24 h after intratracheal administration of LPS.Positive correlation was observed between the increases in PDE activity and TNF-a production,'and the ratio of TNF-a/IL-10.Selective PDE4 inhibitors piclamilast significantly inhibited the inflammation and cAMP-PDE activity in lung after intratracheal administration of LPS. So, Piclamilast could improve LPS induced ALI in rats, its improvement was associated with reducing PDE4 activity and modulating the balance between TNF-a and IL-10.