Mode of action and antiproliferative therapeutic potential of the endogenous serine elastase inhibitor Elafin in pulmonary arterial hypertension

内源性丝氨酸弹性蛋白酶抑制剂 Elafin 在肺动脉高压中的作用方式和抗增殖治疗潜力

• 批准号: 231840359
• 负责人: Dr. Jan Kristoff Hennigs
• 金额: --
• 依托单位: Rabinovitch Laboratory for Cardiopulmonary Research
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/231840359?language=en
• 关键词: Mode; action; antiproliferative; therapeutic; potential

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by increased pulmonary vascular resistance and pressure. Impaired pulmonary hemodynamics lead to right ventricular insufficiency and right heart failure, which may cause patients’ death.Malfunction of pulmonary arterial (PA) endothelial (EC) and smooth muscle cell (SMC) signal transduction and its paracrine regulation triggers pathological remodeling of pulmonary arteries. Progressive PA obliteration and vascular stiffness are caused by an inflammatory disequilibrium of apoptosis and proliferation of PA EC & PA SMC as well as defective extracellular matrix (ECM) synthesis resulting in increased PA resistance and pressure. Now, there is emerging evidence in mice and in patients with PAH that these features are related to PA SMC production of neutrophil elastase (NE). Degradation of vascular elastin induces release of mitogens from the ECM, recruits inflammatory cells to the vessel wall and increases the apoptotic susceptibility of PA EC eventually promoting deregulated PA angiogenesis. So far, approved PAH medications mainly cause PA vasodilation - FDA/EMEA approval for primarily antiproliferative therapeutics is pending. In addition, translation of antiproliferative drugs (such as tyrosine kinase inhibitors) into clinical use in PAH has recently experienced some set backs due to unexpected cardiopulmonary side effects in humans.Therefore, it is necessary to (a) thoroughly characterize novel antiproliferative approaches and (b) predict their therapeutic potential in humans. Elafin might be such a new antiproliferative drug. It is an endogenous inhibitor of NE already shown to reverse PAH remodeling in animal models by a yet not fully understood mode of action. The present project is intended to further identify the underlying cellular mechanisms of Elafin in PA EC and PA SMC from PAH patients and to predict its therapeutic potential in humans. Therefore, the effect of Elafin on pulmonary vascular remodeling is studied in a novel inflammatory PAH rat model that closely resembles pathophysiological changes in humans. Secondly, PA EC and PA SMC isolated from PAH patients will be used to further characterize Elafin’s mode of action. Finally, the therapeutic potential of Elafin will be tested in lung organ cultures from PAH patients to preclinically estimate the translational success in order to pave the way for clinical trials in the future.

肺动脉高压（PAH）是一种以肺血管阻力和压力增加为特征的危及生命的疾病。肺血流动力学异常可导致右心功能不全和右心衰竭，并可导致患者死亡;肺动脉内皮细胞（EC）和平滑肌细胞（SMC）信号转导及其旁分泌调节功能障碍可引发肺动脉病理性重构。进行性PA闭塞和血管僵硬是由PA EC和PA SMC的细胞凋亡和增殖的炎性不平衡以及导致PA阻力和压力增加的有缺陷的细胞外基质（ECM）合成引起的。现在，在小鼠和PAH患者中有新的证据表明，这些特征与PA SMC产生中性粒细胞弹性蛋白酶（NE）有关。血管弹性蛋白的降解诱导有丝分裂原从ECM释放，招募炎性细胞到血管壁，并增加PA EC的凋亡易感性，最终促进PA血管生成失调。到目前为止，批准的PAH药物主要引起PA血管舒张- FDA/EMEA批准主要用于抗增殖治疗。此外，抗增殖药物（如酪氨酸激酶抑制剂）转化为PAH的临床应用，最近由于在人体中出现意外的心肺副作用而经历了一些挫折，因此，有必要（a）彻底表征新型抗增殖方法，（B）预测其在人体中的治疗潜力。Elafin可能是一种新型的抗增殖药物。它是一种内源性NE抑制剂，已在动物模型中显示可通过尚未完全了解的作用模式逆转PAH重塑。本项目旨在进一步确定Elafin在PAH患者PA EC和PA SMC中的潜在细胞机制，并预测其在人体中的治疗潜力。因此，在与人类病理生理学变化非常相似的新型炎性PAH大鼠模型中研究了Elafin对肺血管重塑的影响。其次，从PAH患者中分离的PA EC和PA SMC将用于进一步表征Elafin的作用模式。最后，将在PAH患者的肺器官培养物中测试Elafin的治疗潜力，以临床前评估转化成功，为未来的临床试验铺平道路。