EndOxy in Flame – Influence of a Biohybrid Lung on Inflammatory Pathways and Immune System-Endothelial Cell-Interaction

火焰中的 EndOxy â 生物混合肺对炎症途径和免疫系统-内皮细胞相互作用的影响

• 批准号: 447717028
• 负责人: Professor Dr. Stefan Jockenhövel
• 金额: --
• 依托单位: Klinik für Kinder- und Jugendmedizin
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/447717028?language=en
• 关键词: EndOxy; Flame; Influence; Biohybrid; Lung

Extracorporeal membrane oxygenation (ECMO) is an adequate therapy for the treatment of acute lung failure. It could serve as a suitable option in chronic lung failure as well, if the obstacles towards an implantable lung are cleared. An example of acute lung failure is the Acute Respiratory Distress Syndrome (ARDS) in which ECMO is used for bridging to recovery, while the main reason for chronic lung failure is Chronic Obstructive Pulmonary Disease (COPD). For the latter, an (implantable) lung replacement would be required as long-term treatment option.However, the long-term use of ECMO systems and their development towards an implantable lung device is mainly limited by failure of the oxygenator device. This in turn is due to the poor hemocompatibility of the gas exchange membranes, which are in direct contact with the blood. As a result, unspecific protein binding to the gas exchange membrane leads to a significant decrease of gas transfer performance and thus, a replacement of the device is required after days to some weeks. In addition, the artificial material induces a systemic inflammatory response with yet undefined consequences for the human body. Endothelial cell lining of the gas exchange membranes (so-called endothelialization) seems to be a promising approach to overcome these limitations and opens the gate towards an implantable lung. The active endothelial cell layer acts as a natural biointerface for the contacting blood phase. Nevertheless, the role of the endothelial cell lining in such biohybrid systems with regard to acute and chronic inflammatory responses is currently unknown to our knowledge. Similarly, the reaction of the endothelial cell lining in the setting of low-grade inflammation in COPD and high-grade inflammation during ARDS and COPD exacerbations is unknown. Therefore, the aim of the project is to study the effect of the endothelial cell layer on inflammation in peripheral blood and vice versa in homeostatic conditions, in low-grade and high-grade inflammatory conditions. To evaluate the inflammatory properties, we will perform (i) flow cytometric analysis of early signaling events combined with (ii) transcriptomic analyses of isolated blood cells as well as endothelial cells during ECMO in miniaturized biohybrid lung models. This will result in identification of pathways that will be (iii) verified on the protein level and can be targeted by small molecules. The combination of these methods will provide information about superiority or inferiority of endothelialized devices regarding inflammation in acute and chronic conditions and will identify possible pathways that can be targeted by pharmaceutical approaches.

体外膜肺氧合(ECMO)是治疗急性肺功能衰竭的有效方法。如果移植肺的障碍被清除，它也可以作为慢性肺衰竭的合适选择。急性肺衰竭的一个例子是急性呼吸窘迫综合征(ARDS)，其中ECMO用于过渡到康复，而慢性肺衰竭的主要原因是慢性阻塞性肺疾病(COPD)。对于后者，需要(可植入的)肺置换作为长期治疗选择。然而，ECMO系统的长期使用及其向植入性肺装置的发展主要受到氧合器装置故障的限制。这反过来又是由于与血液直接接触的气体交换膜的血液相容性差所致。因此，与气体交换膜结合的非特异性蛋白质导致气体传输性能的显著下降，因此，需要在几天到几周后更换该装置。此外，这种人造材料会引发全身炎症反应，对人体的影响尚不明确。气体交换膜的内皮细胞衬里(所谓的内皮化)似乎是克服这些限制的一种有前途的方法，并打开了通往植入性肺的大门。活跃的内皮细胞层作为接触血液阶段的天然生物界面。然而，内皮细胞衬里在这种生物杂交系统中在急性和慢性炎症反应中的作用目前尚不为我们所知。同样，在慢性阻塞性肺疾病的低度炎症和急性呼吸窘迫综合征和慢性阻塞性肺病加重期间，内皮细胞衬里的反应也是未知的。因此，该项目的目的是研究内皮细胞层对外周血炎症的影响，在动态平衡条件下，在低级别和高级别炎症条件下，反之亦然。为了评估炎症特性，我们将在微型生物杂交肺模型中进行(I)早期信号事件的流式细胞术分析结合(Ii)ECMO过程中分离的血细胞和内皮细胞的转录分析。这将导致识别将(Iii)在蛋白质水平上验证并可被小分子靶向的途径。这些方法的结合将提供有关内皮化设备在急性和慢性条件下炎症方面的优势或劣势的信息，并将确定药物方法可以靶向的可能途径。