Role of ADAM17 in MDSC-Mediated Development of Pulmonary Hypertension

项目总结

PROJECT SUMMARY While it is known that a reduction in leukocyte recruitment through inhibition of chemokine receptor CXCR2 attenuates development of pulmonary hypertension (PH) in murine models of disease – and that activated pep- tidase ADAM17 levels are associated with improved vascular remodeling – the role of ADAM17 in CXCR2- mediated myeloid cell trafficking leading to the development of PH is unknown. There is an urgent need to close this gap in knowledge because, until accomplished, immunotherapeutic modulation of myeloid-derived suppres- sor cell (MDSC) contribution to the development of pulmonary vascular disease will remain beyond reach. The overall objective of the proposed experiments is to define the contribution of ADAM17 in polymorphonuclear- MDSC (PMN-MDSC) recruitment within the lung vasculature. The central hypothesis is that reduced ADAM17 expression and activity by PMN-MDSC is necessary for recruitment of these cells to the pulmonary vasculature leading to PH. The scientific premise for this hypothesis has been formulated on the basis of preliminary data demonstrating that PMN-MDSC expressing CXCR2 are necessary for development of PH in animal models of disease, and that this circulating cell population is present to a higher degree in whole blood of IPF patients. Additionally, ADAM17 levels inversely correlate with CXCR2 expression, and are associated with development of severe PH. The rationale for the proposed research is that, upon completion of the studies it will be possible to apply current MDSC-targeted therapies to disease prevention and treatment, as well as inform potential harms in the use of ADAM17-targeted treatments for other diseases. The central hypothesis will be tested by pursuing the following specific aims: 1) test the hypothesis that ADAM17 expression and functional activity is differentially regulated in PMN-MDSC isolated from patients with PH and idiopathic pulmonary fibrosis (IPF), and 2) test the hypothesis that ADAM17 expression by PMN-MDSC protects against pathologic pulmonary vascular remodel- ing. In the first aim, peripheral blood samples from patients with IPF with and without PH will be collected, in order to define a MDSC profile in patients with disease and controls, based upon flow cytometric analysis for MDSC sub-types. Cell populations will then be characterized for allelic discrimination of an identified biomarker candidate, in addition to assessment of ADAM17 functional activity, including shedding and proteolytic activity. In the second aim, wild type and transgenic mice with deletion of ADAM17 in myeloid-derived cells (LysM.Cre- ADAM17fl/fl mice) will be used to determine the effect tissue-specific gene expression will have on the develop- ment of PH in two models of disease (bleomycin-induced pulmonary fibrosis and chronic hypoxia). Upon com- pletion, the contribution of this study will be significant because it represents a translatable strategy to improve clinical outcomes through prevention of MDSC trafficking to the lung. The proposed research is innovative be- cause it represents a substantive departure from the status quo by shifting focus from vasodilator therapy to a fine-tuned immunoregulatory mediator, MDSC, in the pathobiology of PH secondary to IPF.