大鼠急性肺损伤模型肺组织中磷酸二酯酶4活性的变化  

The changes of phosphodiesterase-4 activity in rat acute lung injury

作　　者：郑绪阳[1] 谢强敏[1] 杜晓刚[1] 章辉[1] 陈季强[1] 

机构地区：[1]浙江大学医学院呼吸药理实验室,浙江杭州310031

出　　处：《中国药理学通报》2006年第7期844-848,共5页Chinese Pharmacological Bulletin

基　　金：浙江省科技厅重大科技攻关资助项目(No2005C21072);浙江省自然科学基金重点资助项目(NoZ204198)

摘　　要：目的观察磷酸二酯酶4(PDE4)、肿瘤坏死因子-α(TNF-α)和炎症细胞浸润在急性肺损伤过程中的变化规律,以及它们之间的相关性。方法脂多糖(LPS)诱导大鼠急性肺损伤(ALI),高效液相法(HPLC)测定肺组织PDE4活性、ELISA法检测TNF-α含量,常规细胞形态学检测中性粒细胞在支气管肺泡灌洗液(BALF)和肺组织中的浸润变化。结果气道内滴入LPS,1 h后肺组织中PDE4活性开始增加,6 h达到峰值,与对照组相比(P<0.01),24 h后开始回落。支气管肺泡灌洗液(BALF)的白细胞总数和中性粒细胞数的变化与PDE4活性变化相关(r=0.83,P<0.05),2 h后开始增加,6 h达到峰值,48 h后回落接近滴入LPS前。肺组织匀浆的TNF-α含量在LPS滴入后迅速上升,2 h达到峰值,24 h后开始回落,其上升先于前两者。在LPS滴入6 h测定抗超氧阴离子自由基(O.2)和中性粒细胞髓过氧化酶(MPO)水平也明显上升。给予PDE4抑制剂RP73-401(piclamilast)后,肺组织中PDE4活性与TNF-α含量均下降,肺部炎症也得到改善,与损伤后6 h相比差异有显著性(P<0.01)。结论气道内滴入LPS后肺组织中PDE4活性迅速上升,并与TNF-α上升有一定的相关性,运用PDE4抑制剂后,二者水平均明显降低。PDE4和TNF-α升高可能诱导中性粒细胞聚集和过氧化反应的因素,提示PDE4抑制剂可能是一个治疗ALI的重要靶点。Aim To investigate the changes of phosphodiesterase-4 （PDF4, type 4 cAMP-specific PDE） activity, TNF-α and neutrophil recruitment in experimental rat lung injury （ALI）. Methods ALI in the rat was induced by lipopolysacdharide （LPS）. PDFA activity was measured with HPLC, and the level of TNF-α was detected with ELISA, neutrophil infiltration in bronchoalveolar lavage fluid （BALF） and lung tissues was detected by cell count and morphological analysis. Result Lung tissue PDF4 activity significantly increased as early as 1 h, peaked 6 h, and then markedly lowered at 24 h after intratracheal administration of LPS, while there was a same time-course change of total white cell and neutrophil in the BALF （ r = 0. 83, P 〈 0. 05 ）. TNF-α level rapidly peaked 2 h and lowered 24 h after intratracheal administration with LPS, its increasing was earlier than that of PDFA activity and inflammatory cells. The level of myeloperoxidase （MPO） and O2 markedly increased at 6 h after intratracheal administration with LPS. RP73-401 （Piclamilast）, a PDFA inhibitor attenuated the LPS induced lung ALI in rat. Conclusion The level of PDFA activity sharply increases after intratracheal administration with LPS, and there is correlation between the increased PDFA and TNF-α, they are involved in the neutrophil recruitment and peroxidation in the lung tissue. It indicats that PDFA inhibitor is a potentially important target in ALl treatment.

关 键 词：急性肺损伤 磷酸二酯酶4 脂多糖 肿瘤坏死因子-α 中性粒细胞. 

分 类 号：R-332[医药卫生] R322.35