Recruitment and activation of fibroblasts in lung allografts undergoing chronic injury

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For most severe interstitial lung diseases, lung transplantation (LTx) currently provides the only therapeutic option. The bronchiolitis obliterans syndrome (BOS) has to be considered as the main cause for a world wide 5-year-survival after LTx below 50%. We could demonstrate that recipient-derived fibroblasts of bone marrow origin immigrate and significantly contribute to fibrotic bronchial obliteration in LTx. This proposal aims to investigate the mechanisms which govern the recruitment of recipient-derived fibroblast precursor cells and activate them to proliferation and matrix production. Combined laser-microdissection and quantitative real-time PCR together with double fluorescence confocal laser-microscopy will be used to determine the activation status of fibroblasts and to identify cellular sources of fibrogenic cytokines. Micro-RNA profiles of quiescent and activated fibroblasts will be established employing a newly developed miRNA-array. Fibroblast-specific RNAs will be determined in the mononuclear cell fraction of peripheral blood to estimate circulating fibroblast precursors and will be correlated to functional and clinical outcome data. Besides identification of signals which attract fibroblast precursors to the lung we expect to establish novel tissue-based and blood-based prognostic markers to monitor fibrotic remodelling in lung transplants.