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

体外膜氧合（ECMO）是治疗急性肺衰竭的有效方法。如果植入肺的障碍被清除，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用于桥接恢复，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，将需要（植入式）肺替代物作为长期治疗选择。然而，ECMO系统的长期使用及其向植入式肺装置的发展主要受到氧合器装置失效的限制。这反过来又是由于直接与血液接触的气体交换膜的血液相容性差。因此，非特异性蛋白质与气体交换膜结合导致气体传输性能显著降低，因此，需要在几天到几周后更换设备。此外，这种人造材料会引起全身炎症反应，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）似乎是一种很有前途的方法，可以克服这些限制，并为植入式肺打开大门。活跃的内皮细胞层作为接触血相的天然生物界面。然而，内皮细胞衬里在这种生物杂交系统中关于急性和慢性炎症反应的作用目前尚不清楚。同样，内皮细胞内膜在COPD低级别炎症和ARDS和COPD加重期间高级别炎症的反应尚不清楚。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，反之亦然，在稳态条件下，在低级别和高级别炎症条件下。为了评估炎症特性，我们将在小型生物混合肺模型中进行(i)早期信号事件的流式细胞分析，并结合（ii） ECMO期间分离的血细胞和内皮细胞的转录组学分析。这将导致识别途径，这些途径将在蛋白质水平上进行（iii）验证，并且可以被小分子靶向。这些方法的结合将提供关于急性和慢性炎症的内皮化装置的优势或劣势的信息，并将确定可以通过药物方法靶向的可能途径。

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.