Reversing mechanical stress induced remodelling in idiopathic pulmonary fibrosis

特发性肺纤维化(IPF)是一种致命性疾病，平均生存时间为3年。迫切需要新的治疗方案。IPF的特征是肺泡室的巨大重塑，导致肺泡的丢失，并被无功能的替代组织和疤痕取代。机械应力从根本上与IPF的发病机制有关，并被认为是通过激活转化生长因子-β来驱动疾病。然而，机械应力引起的确切机制还只是一个初步的了解。该计划旨在应用分子生物学和新的成像技术研究IPF中机械负荷增加引起的机制。重点在于机械应力诱导的转化生长因子-β信号转导以及avbeta6整合素和CXCR4在这方面的作用。在患有肺纤维化的小鼠和人类中，CXCR4和avbeta6整合素将通过正电子发射断层扫描(PET)在体内进行成像，并与细胞和分子生物学结果相关联。此外，我们将使用器官护理系统(OCS)，通过基于计算机断层扫描(CT)的新开发算法，对移植的IPF肺中的机械应力进行成像。在我们所取得的成就的基础上，我们将开发新的治疗战略，利用与阿尔法发射体绑定的CXCR4、avbeta6和PDGF无线电核示踪剂。治疗效果将在人源化的小鼠模型和使用OCS的移植肺中进行测试。此外，额外的体膜氧合(ECMO)和器官护理系统将被评估为暂时的机械应力卸载，以允许反向重塑。

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with a mean survival time of 3 years. New treatment options are urgently warranted. IPF is characterized by a vast remodeling of the alveolar compartment which results in a loss of alveoli and replacement by non-functional replacement tissue and scarring. Mechanical stress is fundamentally linked to the pathogenesis of IPF and thought to drive the disease by TGF-beta activation. The exact mechanisms induced by mechanical stress however are only rudimentarily understood. The intended project aims to investigate mechanisms induced by increased mechanical load in IPF applying molecular biology and new imaging techniques. The focus lies on TGF-beta signaling induced by mechanical stress and the role of avbeta6 integrin and CXCR4 in this context. In mice and humans with pulmonary fibrosis CXCR4 and avbeta6 integrin will be imaged by positron emission tomography (PET) in vivo and correlated with cell and molecular biology findings. In addition, we will use the organ care system (OCS) to image mechanical stress in explanted IPF lungs by newly developed algorithms based on computer tomography (CT) scanning. On the basis of our achievements we will develop new therapeutical strategies which utilize the CXCR4, avbeta6 and PDGF radio nuclear tracers bound to alpha emitters. Treatment effects will be tested in a humanized mice model and in explanted lungs using the OCS. Moreover extra corporal membrane oxygenation (ECMO) and the organ care system will be evaluated as temporal unloading of mechanical stress to allow reverse remodelling.