Cell specific role of proteolytic shedding by the metalloproteinases ADAM10 and ADAM17 in chronic lung infammation

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Acute and chronic inflammation is driven by the activity of surface expressed effector molecules and the release of pro-inflammatory mediators. The metalloproteinases ADAM10 and ADAM17 mediate the cleavage and release of several surface molecules (cytokines, receptors, chemokines, growth factors and adhesion molecules) regulating vascular permeability and recruitment of leukocytes. Using cell-specific knockout mice we have demonstrated a crucial contribution of ADAM10 and ADAM17 towards acute lung inflammation induced by intranasal application of LPS or acid. While endothelial ADAM17 activity was related to the cleavage of adhesion molecules and permeability regulation, smooth muscle ADAM17 function was linked to the shedding of growth factors and subsequent transactivation of the cells. In leukocytes ADAM10 but not ADAM17 contributes to acute lung inflammation by promoting leukocyte migration, adhesion and signalling.Besides their proinflammatory function in actute lung inflammation, the contribution of ADAM10 and ADAM17 towards later stages of chronic inflammation such as lung fibrosis and allergic asthma remains completely unclear. Here we aim to investigate the possible role of ADAM10 and ADAM17 during the course of chronic lung inflammation and their function as switch molecules deciding between progression and resolution/repair. Our first experiments indicate that endothelial ADAM10 acts proinflammatory in early acute inflammation but holds a protective role at later stages of inflammation. Our hypothesis therefore is that both proteases differentially regulate early and late phases of inflammation by shedding of surface molecules in a cell-specific manner. We will therefore study the regulation and activity of ADAMs in different phases of lung inflammation and fibrosis development induced in mice by intratracheal instillation of bleomycin and investigate the role of cell-specific knockout of ADAM10 and ADAM17 for T cell recruitment, cytokine release, collagen production and tissue remodelling. The activity of the proteases will be linked to the shedding of adhesion molecules, growth factors, Notch and others. Mechanistic analysis on cell migration, permeability, mediator secretion, proliferation, survival, regeneration, and transactivation will be performed with primary human and murine lung cells and leukocytes either from cell-specific knockout mice or after pharmacological or transcriptional suppression of ADAM10 or ADAM17. The same procedure will be used to investigate whether ADAM10 and ADAM17 also control early and late phases of asthmatic lung inflammation in response to OVA immunization and challenge by general or disease specific pathways. This study shall investigate the time- and cell-dependent functional switch of ADAM proteases in the course from actute to chronic lung inflammation. This should have important implications for the development of antinfammatory treatment strategies with ADAM inhibitors.