Dent G, Magnussen H, Rabe K F
Krankenhaus Grosshansdorf, Zentrum für Pneumologie und Thoraxchirurgie, LVA Hamburg, Grosshansdorf, Germany.
Lung. 1994;172(3):129-46. doi: 10.1007/BF00175942.
Although theophylline has been used in the treatment of lung diseases, particularly bronchial asthma, since the nineteenth century, the mechanisms underlying its effectiveness remained poorly understood until quite recently. The identification of cyclic nucleotide phosphodiesterase (PDE)--the enzyme responsible for breaking down cyclic AMP and cyclic GMP within cells--as a target for methylxanthines such as theophylline led to a research effort that has resulted in the characterization of multiple forms of the PDE enzyme and the development of selective inhibitors for some of these forms. Using these drugs, it has been possible to identify the PDE "isoenzymes" in a number of tissues and cells and to demonstrate the functional effects of the inhibition of different PDEs upon these tissues. Studies on the smooth muscle of human airways and pulmonary arteries have identified isoenzyme-selective PDE inhibitors that are effective broncho- and vasorelaxants in vitro, and it is hoped that these agents may be effective in relieving airway obstruction and pulmonary hypertension in patients. In addition, selective inhibitors of certain PDE isoenzymes suppress the proinflammatory functions of a range of immune cells, including the lung mast cell and the alveolar macrophage. Selective inhibitors of PDE isoenzymes are beginning to undergo clinical trials for the treatment of asthma. The advancing understanding of the PDE distribution in the lung and the ever more precise characterization of distinct enzyme proteins should allow the development of site-selective drugs for the treatment of lung diseases, while minimizing the systemic side effects associated with nonselective PDE inhibitors such as theophylline.
自19世纪以来，茶碱就被用于治疗肺部疾病，尤其是支气管哮喘，但直到最近，其起效的潜在机制仍鲜为人知。环核苷酸磷酸二酯酶（PDE）——负责在细胞内分解环磷酸腺苷（cAMP）和环磷酸鸟苷（cGMP）的酶——被确定为茶碱等甲基黄嘌呤类药物的作用靶点，这引发了一项研究工作，最终对多种形式的PDE酶进行了表征，并开发出了针对其中一些形式的选择性抑制剂。使用这些药物，已经能够在许多组织和细胞中鉴定出PDE“同工酶”，并证明抑制不同PDE对这些组织的功能影响。对人类气道和肺动脉平滑肌的研究已经确定了同工酶选择性PDE抑制剂，这些抑制剂在体外是有效的支气管和血管舒张剂，人们希望这些药物在缓解患者气道阻塞和肺动脉高压方面可能有效。此外，某些PDE同工酶的选择性抑制剂可抑制一系列免疫细胞的促炎功能，包括肺肥大细胞和肺泡巨噬细胞。PDE同工酶的选择性抑制剂已开始用于哮喘治疗的临床试验。对肺部PDE分布的进一步了解以及对不同酶蛋白越来越精确的表征，应该能够开发出用于治疗肺部疾病的位点选择性药物，同时将与茶碱等非选择性PDE抑制剂相关的全身副作用降至最低。
