Pfizer Global Research and Development, Biology Laboratories, Fresnes, UK.
Eur Respir J. 2012 Mar;39(3):582-8. doi: 10.1183/09031936.00102610. Epub 2011 Nov 16.
Type 7 phosphodiesterases (PDE7) are responsible for the decrease of intracellular cyclic AMP (cAMP) in many cells involved in allergic asthma by suppressing their potential to respond to many activating stimuli. The elevation of intracellular cAMP has been associated with immunosuppressive and anti-inflammatory activities and represents a potential treatment of asthma. Our aim was to evaluate the impact of the deletion of the murine phosphodiesterase (PDE)7B gene and then to evaluate the efficacy of a newly described selective PDE7A and -B inhibitor on an ovalbumin (OVA)-induced airway inflammation and airway hyperreactivity (AHR) model in mice. Inflammation was determined 72 h after single OVA challenge or 24 h after multiple challenges by the relative cell influx and cytokine content in bronchoalveolar lavage fluid. AHR and immunoglobulin E levels in serum were determined after multiple challenges. For the first time, we have demonstrated that the deletion of the PDE7B gene or the pharmacological inhibition of PDE7A and -B had no effect on all the parameters looked at in this model. These results highlight the absence of any implication of the PDE7 enzyme in our model.
7 型磷酸二酯酶（PDE7）通过抑制其对许多激活刺激的反应能力，负责降低参与变应性哮喘的许多细胞内的环磷酸腺苷（cAMP）。细胞内 cAMP 的升高与免疫抑制和抗炎活性有关，代表了哮喘的一种潜在治疗方法。我们的目的是评估删除小鼠磷酸二酯酶（PDE）7B 基因的影响，然后评估新描述的选择性 PDE7A 和 -B 抑制剂在卵清蛋白（OVA）诱导的气道炎症和气道高反应性（AHR）模型中的功效在小鼠中。在单次 OVA 挑战后 72 小时或多次挑战后 24 小时，通过支气管肺泡灌洗液中相对细胞流入和细胞因子含量来确定炎症。在多次挑战后测定血清中的 AHR 和免疫球蛋白 E 水平。我们首次证明，PDE7B 基因缺失或 PDE7A 和 -B 的药理学抑制对该模型中观察到的所有参数均无影响。这些结果突出表明 PDE7 酶在我们的模型中没有任何作用。
