| Phosphodiesterase 4 (PDE4) has been suggested to a critical factor in the pathogenesis of inflammation by metabolizing cAMP in human leukocytes, endothelium and epithelium. Inhibitors of phosphodiesterase-4 (PDE4) are efficacious for allergic asthma in animal models and have shown some efficacy in human asthma. Regulation of PDE4 in allergy and asthma has been widely investigated in blood leukocytes with discrepant results. In this study, we investigated PDE4 the PDE4 activity and expression, the relationship between the inflammation and cAMP- activity in the lungs in rat models of allergic asthma., and potential interventions of PDE4 inhibitors and antiinflammatory drugs in the reduction of lung inflammation and goblet cell hyperplasia in allergic rats. The main contents are divided into some sections as follows:1. The total leukocyte number and eosinophil number in bronchoalvelar lavegar fluid in lungs significantly increased in OVA-sensitized and challenged allergic rat. Those OVA-induced changes were prevented by pretreatment with PDE inhibitor in a dose-related patterns and with glococorticosteroid.2. Ovalbumin sensitization and challenge significantly increased pulmonary resistance (RL) of pulmonary function and decreased dynamic lung compliance (Cdyn).The increases in pulmonary resistance and decrease in dynamic lung compliance were suppressed by the PDE4-selective inhibitor rolipram or the corticosteroid drug dexamethasone.3. Ovalbumin sensitization and challenge significantly increased lung interleukin (IL)-4 production. The increases in IL-4 production were both suppressed by thePDE4-selective inhibitor rolipram or the corticosteroid drug dexamethasone. A highly significant correlation was observed between the increases in PDE activity and IL-4 production.4. cAMP-PDE enzyme activity in the lung was significantly increased by the sensitization and challenge. Those OVA-induced changes were prevented by pretreatment with PDE inhibitor in a dose-related patterns and with glococorticosteroid.5. The proportion of PDE4 increased, while the proportion of PDE3 decreased in the total cAMP-PDE activity in the lung of allergic rats.6. Lung histology showed an increased infiltration of inflammatory cells in the perivascular and peribronchial spaces, and goblet cell hyperplasia in the OVA-sensitived and challgened allergic rats. A significant correlation was observed between the increases in cAMP-PDE activity and inflammation in the lung. Those OVA-induced changes were prevented by pretreatment with PDE inhibitor in a dose-related patterns and with glococorticosteroid.7. Abundant and overlapping expression of PDE4, PDE4A, and PDE4D have been observed in inflammatory cell and bronchial epithelium and smooth muscle of blood vessel and airway. While the highest expression for PDE4B presented a more restricted distribution, limited to inflammatory cell, and 4C limited to bronchial epithelium and airway smooth muscle. OVA sensitization and challenge caused an increase in PDE4, PDE4A, PDE4B, PDE4C and PDE4D expression(P<0.05 or 0.01). Dexamethasone can obvious decrease the expression of PDE4 subtype(P<0.05).8. OVA sensitization and challenge significantly increased the levels of PDE 4A, 4C and 4D mRNAs, as compared with normal rats (p<0.05 or <0.01). This result strongly suggests that the increased cAMP-PDE activity might be, at least in part, due to enhanced PDE4 gene expression by antigen sensitization and challenge. Those changes were prevented by pretreatment with PDE inhibitor in a dose-related patterns and with glococorticosteroid.9. Tracheal tissues from OVA-sensitized and challenged rats had significantly increased tensions as compared with those from normal rats upon stimulation with methacholine(0.01 μM - 1 mM). Salbutamol reversed the methacholine-induced contraction in a concentration-dependent manner. There was an increased relaxation of methacholine-induced contraction by salbutamol in normal tracheal tissues as compared with tracheal tissues from OVA-sensitized and... |
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