ADAM10 and 17 protease - new key points in acute pulmonary inflammation

ADAM10和17蛋白酶——急性肺部炎症的新关键点

• 批准号: 509100215
• 负责人: Professorin Dr. Franziska M. Konrad
• 金额: --
• 依托单位: Klinik für Anaesthesiologie und Intensivmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/509100215?language=en
• 关键词: ADAM10; 17; protease; new; key

The acute respiratory distress syndrome (ARDS) is a frightening complication in intensive care units. This life-threatening disease is still associated with a mortality rate of up to 40%. Despite decades of research, the only therapeutic options are just supportive (positioning and ventilation therapy) and not causal. The central pathomechanism and key point in the early phase of ARDS, is the uncontrolled accumulation of activated polymorphonuclear neutrophils (PMNs). This uncontrolled, excessive migration of PMNs leads to tissue destruction in the lung. Experimental research showed that modulation of PMN migration has protective effects. Thereby, it is known that platelets play a critical role in terms of PMN migration. In the working group of the applicant, a flow cytometry method is used to detect PMNs in the different compartments of the murine lung. So, it is possible to distinguish between PMNs intravascular, attached to the endothelium, interstitial or in the alveolar space. Therefore, detailed investigations of the distinct PMN migration steps are possible. The ADAM proteases (A Disintegrin And Metalloproteinase) are a group of enzymes, who degrade proteins and peptides in the extracellular space and either activate or inactive them by proteolysis. ADAM10 and 17 are expressed in the lung and, additionally, play a crucial role in terms of the initial immune defense. Previous publications and preliminary work of the applicant suggest protective effects by inhibiting both proteases in terms of acute pulmonary inflammation, but still the existing data is conflicting. By using specific genetically generated mice, the impact of ADAM10 and 17 on acute pulmonary inflammation will be investigated within the planned project. Mice with either ADAM10 or 17 depleted on PMNs, platelets or endothelial cells, will be used to determine their impact on the two key characteristics of acute pulmonary inflammation - PMN migration and microvascular permeability. Hence, it can be differentiated between the two proteases and their impact on the distinct single cells. This new knowledge will fundamentally increase the pathophysiological understanding, and also helps to identify which protease could be a target for which part of the inflammation. For example, inhibiting ADAM10 could have an impact on microvascular permeability and ADAM17 on PMN migration. Measurements of lung physiology and the application of specific adam inhibitors at different time points in terms of the inflammation, and also nebulized and therefore topical application is supposed to increase the clinical impact of the murine investigations.

急性呼吸窘迫综合征（ARDS）是重症监护室中一种可怕的并发症。这种危及生命的疾病仍然与高达40%的死亡率相关。尽管经过数十年的研究，唯一的治疗选择只是支持性的（定位和通气治疗），而不是因果关系。急性呼吸窘迫综合征（ARDS）早期的中心病理机制和关键是活化的中性粒细胞（PMNs）的不受控制的聚集。这种不受控制的、过度的中性粒细胞迁移导致肺中的组织破坏。实验研究表明，调节PMN迁移具有保护作用。因此，已知血小板在PMN迁移方面起关键作用。在申请人的工作组中，使用流式细胞术方法检测鼠肺的不同隔室中的PMN。因此，有可能区分血管内、附着于内皮、间质或肺泡空间中的PMN。因此，详细调查不同的PMN迁移步骤是可能的。ADAM蛋白酶（A Disintegrin And Metalloproteinase）是一组酶，其降解细胞外空间中的蛋白质和肽，并通过蛋白水解激活或灭活它们。ADAM 10和17在肺中表达，此外，在初始免疫防御方面发挥关键作用。申请人先前的出版物和初步工作表明，通过抑制两种蛋白酶在急性肺部炎症方面具有保护作用，但现有的数据仍然相互矛盾。通过使用特定的基因产生的小鼠，ADAM 10和17对急性肺部炎症的影响将在计划的项目中进行研究。将使用在PMN、血小板或内皮细胞上耗尽ADAM 10或17的小鼠来确定它们对急性肺部炎症的两个关键特征- PMN迁移和微血管通透性的影响。因此，可以区分两种蛋白酶及其对不同单细胞的影响。这一新知识将从根本上增加对病理生理学的理解，并有助于确定哪种蛋白酶可能是炎症哪部分的靶标。例如，抑制ADAM 10可能会影响微血管渗透性，抑制ADAM 17可能会影响中性粒细胞迁移。肺生理学的测量和特定adam抑制剂在炎症方面的不同时间点的应用，以及雾化和因此局部应用被认为增加了小鼠研究的临床影响。