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

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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.