Department of Medicine, Anesthesiology, Physiology and Cell Biology, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
Center for Basic Medical Sciences, Graduate School, International University of Health and Welfare, Chiba, Japan.
FASEB J. 2021 Jul;35(7):e21519. doi: 10.1096/fj.202001966RR.
Globally, COPD remains a major cause of disability and death. In the United States alone, it is estimated that approximately 14 million people suffer from the disease. Given the high disease burden and requirement for chronic, long-term medical care associated with COPD, it is essential that new disease modifying agents are developed to complement the symptomatic therapeutics currently available. In the present report, we have identified a potentially novel therapeutic agent through the use of a high throughput screen based on the knowledge that cigarette smoke induces the proteolytic enzyme MMP1 leading to destruction of the lung in COPD. A construct utilizing the cigarette responsive promoter element of MMP-1 was conjugated to a luciferase reporter and utilized in an in vitro assay to screen the NIH Molecular Libraries Small Molecule Repository to identify putative targets that suppressed luciferase expression in response to cigarette smoke extract (CSE). Selective serotonin reuptake inhibitors potently inhibited luciferase expression and were further validated. SSRI treatment suppressed MMP-1 production in small airway epithelial cells exposed to (CSE) in vitro as well as in smoke exposed rabbits. In addition, SSRI treatment inhibited inflammatory cytokine production while rescuing cigarette smoke induced downregulation in vivo of the anti-inflammatory lipid transporter ABCA1, previously shown by our laboratory to be lung protective. Importantly, SSRI treatment prevented lung destruction in smoke exposed rabbits as measured by morphometry. These studies support further investigation into SSRIs as a novel therapeutic for COPD may be warranted.
全球范围内，COPD 仍然是导致残疾和死亡的主要原因。仅在美国，据估计就有大约 1400 万人患有这种疾病。鉴于 COPD 与高疾病负担和对慢性、长期医疗护理的需求相关，开发新的疾病修饰剂以补充目前可用的对症治疗方法至关重要。在本报告中，我们通过使用基于香烟烟雾诱导蛋白水解酶 MMP1 的高通量筛选方法，发现了一种有潜在治疗作用的新药物。该方法利用 MMP-1 的香烟反应启动子元件构建了一个报告基因，然后在体外测定中用于筛选 NIH 分子文库小分子库，以鉴定可能的靶标，这些靶标在受到香烟烟雾提取物（CSE）刺激时可以抑制报告基因的表达。选择性 5-羟色胺再摄取抑制剂（SSRIs）强烈抑制报告基因的表达，并进一步得到验证。SSRI 治疗可抑制体外暴露于 CSE 的小气道上皮细胞中 MMP-1 的产生，以及暴露于香烟烟雾的兔子中的 MMP-1 的产生。此外，SSRI 治疗可抑制炎症细胞因子的产生，同时恢复体内抗炎脂质转运蛋白 ABCA1 的下调，我们实验室先前的研究表明 ABCA1 对肺部具有保护作用。重要的是，SSRI 治疗可防止暴露于香烟烟雾的兔子的肺部破坏，这可以通过形态计量学来衡量。这些研究支持进一步研究 SSRI 作为 COPD 的一种新的治疗方法，可能是合理的。
