Changes Of Phosphodiesterase 4 Activity In Chronic Obstructive Pulmonary Disease Of Rat And Effects Of Its Selective Inhibitor

BackgroundChronic obstructive pulmonary disease (COPD) is a chronic inflammatory progressive disease in which airflow limitation is reversible incompletely. Phosphodiesterase 4 (PDE4), the specific of cAMP and cGMP hydrolase, can hydrolyze cAMP and cGMP in cell into unactive mononucleotide. Therefore PDE and its inhibitor could have effects on metabolism of organies by regulating the intracellular level of cAMP and cGMP. PDE4 is the main regulator of metabolism of cAMP. In addition, it is the main PDE isoenzyme in inflammatory and immunologic cells and the main PDE isoenzyme in lung tissue. PDE4 is the main type of PDEs located in neutrophil, CD8+ lynphocyte and macrophage, therefore the PDE4 inhibitors could be effective in controling the inflammatory reaction of COPD.The key to the question that how the PDE4 activity changes in COPD is uncertain. The antiinflammatory effect of PDE4 inhibitors is generally accepted, but we should do more research to study their effects on other pathophysicologic changes of COPD. MethodsMale SD rats were divided into 6 groups: control group, model group, RP001 1 mg/kg group, RP001 3 mg/kg group, RP001 10 mg/kg group and DXM group. We established the COPD rat model by exposure to cigarette smoking and intratracheal instillation of lipopolysaccharide, which lasted 3 monthes (90d). The rats havereceived drug interventions from the 15th day of the experimental period. The rats in control group didn' receive any intervention. We observed dynamic changes of body weight and measured airway resistance, dynamic lung compliance. The lower of left lungs were stained with hematoxylin and eosin after fixed with 10% formalin. We used light microscope to observe pathologic changes. The PDE4 activity in lung homogenate were measured by HPLC. The activity of SOD and the amount of MDA , two common indexes in estimating oxidation and antioxidation functions of lung, were measured. Results:1. In comparison with control group, the body weight of rats in model group decreased significantly since the 3th week to the 12th week. In comparison with model group, the body weight in RPOOl lmg/kg group increased significantly in the 3th, 4th and 6th week. Meanwhile, in RPOOl 3mg/kg group the significant difference was in the 3th, 4th, 6th, 7th, 8th, 9th, 11th and 12th week. In RPOOl lOmg/kg group the body weight increased significantly from the 3th week to the end, compared with model group. There was no significant diffrernce between DXM group and model group all of the progression.2. In model group, the airway resistance increased significantly and the dynamic lung compliance decreased significantly. All of the drug intervention groups showed amelioration for the changes of airway resistances and dynamic lung compliance.3. In model group, we observed that columnar epithelial cells in bronchuses had partially fallen off. Intensive hyperplasia of goblet cells and muscular layer under mucous membrane in bronchuses and serious infiltration of inflammatory cells underneath mucous membrane were also observed. Thinness, swelling, disruption, destruction of alveolar wall and elastic net, formation of pneumatocele in lungs, which were significant characteristics in COPD, were observed. The pathologic changes of drug intervention groups ameliorated in some extent.4. The activity of PDE4 in model group increased significantly. The activity of PDE4 in all the drug intervention groups, especially in RPOOl lOmg/kg group and DXM group, displayed significant decreases compared with model group.5. The activity of SOD in lung of model group decreased significantly. While the amount of MDA in lung of model group increased significantly. But the two datas ameliorated significantly only in RPOOl 10 mg/kg group in comparison with model group. Conclusions1. The COPD rat model could be established by chronic exposure to cigarette smoking and intratracheal instillation of lipopolysaccharide.2. PDE4 activity in lung increases significantly during the development of COPD in rat. Body weight, pulmonary function, the balance between oxidation and antioxidation and pathologic form of bronchus and lung have significant changes.3. Selective PDE4 inhibitor RPOOl exhibits a significant amelioration for pathophysiologic changes of COPD rat model by reducing PDE4 activity in lung.