Woodside Darren G, Vanderslice Peter
Department of Drug Discovery, Biological Sciences, Encysive Pharmaceuticals Inc., Houston, Texas, USA.
BioDrugs. 2008;22(2):85-100. doi: 10.2165/00063030-200822020-00002.
Chronic obstructive pulmonary disease (COPD) and asthma are inflammatory diseases of the lung where a hallmark feature is excessive leukocyte infiltration that leads to tissue injury. Cell adhesion molecules (e.g. selectins and integrins) play a key role in cell trafficking, and in the lung they regulate leukocyte extravasation, migration within the interstitium, cellular activation, and tissue retention. All selectin family members (including L-selectin, P-selectin, and E-selectin) and many of the beta1 and beta2 integrins appear to be important therapeutic targets, as numerous animal studies have demonstrated essential roles for these cell adhesion molecules in lung inflammation. Not surprisingly, these families of adhesion molecules have been under intense investigation by the pharmaceutical industry for the development of novel therapeutics. Integrins are validated drug targets, as drugs that antagonize integrin alphaIIbbeta3 (e.g. abciximab), integrin alphaLbeta2 (efalizumab), and integrin alpha4beta1 (natalizumab) are currently US FDA-approved for acute coronary syndromes, psoriasis, and multiple sclerosis, respectively. However, none has been approved for indications related to asthma or COPD. Here, we provide an overview of roles played by selectins and integrins in lung inflammation. We also describe recent clinical results (both failures and successes) in developing adhesion molecule antagonists, with specific emphasis on those targets that may have potential benefit in asthma and COPD. Early clinical trials using selectin and integrin antagonists have met with limited success. However, recent positive phase II clinical trials with a small-molecule selectin antagonist (bimosiamose) and a small-molecule integrin alpha4beta1 antagonist (valategrast [R411]), have generated enthusiastic anticipation that novel strategies to treat asthma and COPD may be forthcoming.
慢性阻塞性肺疾病（COPD）和哮喘是肺部的炎症性疾病，其一个标志性特征是白细胞过度浸润导致组织损伤。细胞黏附分子（如选择素和整合素）在细胞转运中起关键作用，在肺部它们调节白细胞渗出、间质内迁移、细胞活化和组织滞留。所有选择素家族成员（包括L-选择素、P-选择素和E-选择素）以及许多β1和β2整合素似乎都是重要的治疗靶点，因为大量动物研究已证明这些细胞黏附分子在肺部炎症中起重要作用。不出所料，制药行业一直在对这些黏附分子家族进行深入研究以开发新型疗法。整合素是已获验证的药物靶点，因为目前美国食品药品监督管理局（FDA）已批准分别用于急性冠状动脉综合征、银屑病和多发性硬化症的拮抗整合素αIIbβ3（如阿昔单抗）、整合素αLβ2（依法利珠单抗）和整合素α4β1（那他珠单抗）的药物。然而，尚无一种药物获批用于与哮喘或COPD相关的适应症。在此，我们概述选择素和整合素在肺部炎症中所起的作用。我们还描述了开发黏附分子拮抗剂的近期临床结果（包括失败和成功的案例），特别强调那些可能对哮喘和COPD有潜在益处的靶点。使用选择素和整合素拮抗剂的早期临床试验取得的成功有限。然而，近期一项针对小分子选择素拮抗剂（比莫西莫司）和小分子整合素α4β1拮抗剂（瓦拉特格拉司[R411]）的II期临床试验取得了阳性结果，这引发了人们的热切期待，即可能即将出现治疗哮喘和COPD的新策略。
