吡拉米司特在大鼠急性肺损伤模型中降低PDE4活性与TNF-α/IL-10平衡有关

目的观察PDE4活性与TNF-α/IL-10平衡在脂多糖(LPS)诱导的大鼠急性肺损伤模型(ALI)中相互关系,探讨选择性磷酸二酯酶4抑制剂吡拉米司特(piclamilast)对ALI的作用及机制。方法脂多糖(LPS)诱导大鼠ALI模型,设对照组、模型组、吡拉米司特组(1、3、10mg.kg-1)和地塞米松组(1mg.kg-1),常规细胞形态学检测肺泡灌洗液(BALF)和肺组织中中性粒细胞的浸润情况,比色法测定BALF中超氧阴离子自由基(O2.)和中性粒细胞髓过氧化酶(MPO),ELISA法检测肺组织中TNF-α和IL-10含量,高效液相(HPLC)法测定肺组织中PDE4活性。结果①吡拉米司特(1、3、10mg.kg-1)灌胃给予能够抑制BAL中MPO、O2.的增加,改善LPS诱导的大鼠ALI模型BALF中的炎症细胞聚集和肺水肿程度,②吡拉米司特可抑制LPS诱导的大鼠ALI肺组织TNF-α上升(P<0.05～0.01),并能明显提高LPS引起的大鼠ALI肺组织IL-10分泌下降,③大鼠ALI模型肺组织中PDE4活性明显上升(P<0.01),吡拉米司特预处理可抑制PDE4活性的上升,而且其对PDE4活性抑制性变化与TNF-α/IL-10比值的变化基本一致。地塞米松1mg.kg-1也能降低TNF-α和升高IL-10水平,调节TNF-α/IL-10平衡关系,但DXM不能抑制PDE4活性的升高。结论TNF-α/IL-10可能是ALI病理生理学的一对重要的平衡性细胞因子。吡拉米司特可能通过抑制PDE4活性,调节TNF-α/IL-10平衡改善LPS诱导的大鼠ALI。

Piclamilast reduced PDE4 activity associated with the balance between TNF-α and IL-10 during acute lung injury in rat

Aim To investigate the effect and mechanism of piclamilast,a selective phosphodiesterase(PDE)4 inhibitor,on rat acute lung injury(ALI)through observing the relationship of the PDE4 activity and the balance between tumor necrosis factor(TNF)-α and interleukin(IL)-10.Method Rat acute lung injury was induced by lipopolysaccharide(LPS),and animals were randomly assigned to six groups:control,model,piclamilast(1,3,10 mg·kg-1)and dexameathone(1 mg·kg-1).Neutrophil in bronchoalveolar lavage fluid(BALF)and lung tissues was detected by cell count and morphological analysis.The activities of myeloperoxidase(MPO)and superoxide anion(O· _2)in BALF were measured by colorimetry.TNF-α and IL-10 levels in the lung tissue were detected with ELISA,and the PDE4 activity was measured by HPLC.Results(1)The LPS-induced increase in neutrophils and lung oedema,MPO and O· _2activities in BAL were significantly reduced by piclamilast pretreatment(P<0.01).(2)The LPS-induced increase in TNF-α release in the lung was significantly reduced by piclamilast pretreatment(P<0.05～0.01).In contrast,IL-10 level in the lung was decreased by LPS but restored by piclamilast,however it was not depended on dosages.(3)The change of PDE4 activity accorded with the ratio of TNF-α/IL-10,dexameathone 1 mg·kg-1 also can reduce the TNF-α and restore the IL-10 level decreased by LPS,however it could not reduce the PDE4 activity in the rat lung in ALI.Conclusion The balance between TNF-α and IL-10 may be important in ALI.Piclamilast could improve LPS induced ALI in rats and its improvement was associated with reducing PDE4 activity and modulating the balance between TNF-a and IL-10.