咯利普兰对大鼠哮喘模型肺组织磷酸二酯酶及IL-4的影响

The effects of rolipram on PDE activity and IL-4 level in the lung tissue of ovalbumin sensitized and repeatedly challenged rats

目的为阐明大鼠哮喘模型肺组织cAMP-PDE活性升高的相关原因和意义,研究了咯利普兰(rolipram,Rol)对大鼠哮喘模型的肺功能、肺组织中磷酸二酯酶(PDE)活性和IL-4含量的影响。方法采用卵白蛋白致敏后重复抗原攻击制备哮喘模型,测定肺功能,肺组织cAMP-PDE活性、PDE4的活性和IL-4含量,分类计数外周血和支气管肺泡灌洗液(BALF)中的白细胞。结果哮喘大鼠肺组织cAMP-PDE及PDE4活性与正常对照组相比均升高(P<0·05),致敏后重复抗原攻击的哮喘大鼠肺组织cAMP-PDE活性中PDE4活性比例较高,约占70%。Rol剂量依赖性增加哮喘大鼠肺顺应性,降低肺阻力,抑制增加的哮喘大鼠肺组织cAMP-PDE和PDE4活性,降低肺组织IL-4含量。以Rol(1mg·kg-1,po)作用最明显。哮喘大鼠的肺组织cAMP-PDE和PDE4活性与IL-4存在相关性(P<0·05)。此外,Rol还能明显抑制哮喘大鼠BALF中和外周血炎症细胞数目,明显抑制BALF中多形核细胞及血中EOS的比例(P<0·05)。结论致敏后重复抗原攻击的哮喘大鼠肺功能明显恶化,肺组织IL-4含量、cAMP-PDE活性明显升高,其中cAMP-PDE活性中以PDE4为主,且cAMP-PDE活性、PDE4活性与肺组织中IL-4密切相关。Rol能有效抑制哮喘大鼠肺组织cAMP-PDE及PDE4活性的升高,降低IL-4含量,改善肺功能。

Aim To illustrate the reason and significance of upregulation of cAMP-PDE activity in the lung of asthmatic rats, we studied the pulmonary function and phosphodiesterase （PDE） activity and IL-4 level in the lung tissue of model rats compared with the control rats, and observed the effects of the classical phosphodiesterase 4 inhibitor rolipram. Methods Ovalbumin sensitized and challenged rats were used as asthmatic model. Aerosol antigen induced inflammatory changes in bronchoalvelar lavegar fluid and peripheral blood were investigated. Dynamic lung compliance and pulmonary resistance were determined using a single chamber whole body plethysmogranph. Lung interleukin （IL）-4 level was determined by ELISA. cAMPPDE and PDFA activity were determined by HPLC. Results The cAMP-PDE and PDFA activity, IL-4 level and total cell counts and eosinophil counts in BALF and peripheral blood in lungs of repeatedly OA challenged and sensitized rats were singnificantly increased than those in the control rats （P 〈 0. 05 ）. Meanwhile, dynamic lung compliance was singnificantly decreased and pulmonary resistance singniflcantly increased. Rolipram （ 1 mg·kg^-1, po） increased dynamic lung compliance and decreased pulmonary resistance of OA sensitized and challenged rats significantly （P 〈 0. 05 ）. Rolipram significantly decreased the increased cAMP-PDE and PDFA activity in lungs of repeatedly OA challenged andsensitized rats. Rolipram （0.3 mg · kg^-1, po） and rolipram （ 1 mg · kg^-1, po） singnificantly decreased the increased IL-4 level of repeatedly OA challenged and sensitized rats （P 〈 0. 05 ）. Rolipram markedly reduced total cell counts and eosinophil counts in BALF and peripheral blood of OA challenged and sensitized rats （P 〈 0. 05 ）. Spearman correlation analysis showed that cAMP-PDE activity, primarily due to PDFA activity in lungs of repeatedly OA challenged and sensitized rats had statistically significant correlation with the IL-4 level （P 〈 0. 05）. Conclusion Rolipram significantly increased dynamic lung compliance and decreased pulmonary resistance, decreased the increased cAMP-PDE activity and IL-4 level in lungs of repeatedly OA challenged and sensitized rats. Moreover, cAMP-PDE activity or PDFA activity had correlation with the IL-4 level.