LSC Abstract – Identification of pathogenic micro RNA (miR) in BOS: A system biology approach

A complex computational pipeline to perform enrichment analysis of miRNAs in pathways was applied to the study of post lung transplant Bronchiolitis Obliterans Syndrome (BOS). The analysis considers the full set of miRNAs annotated in miRBase (version 21), and applies different filtering approaches and statistical analyses to reduce this set and to score the candidate miRNAs with potential involvement in BOS development. In order to validate results of the computational analysis we analyzed, by ISH, two highly ranked miRNAs, miR-21 and miR-34a, in a set of lung tissue samples obtained from 3 patients with BOS and in mesenchymal cells from BAL of lung recipients in stable conditions, or with BOS (0p-3) and, as control, normal skin fibroblasts and primary mesenchymal cells obtained from patients with COP. Preliminary ISH results demonstrated a dysregulation of these miRNAs and its localization in BOS lesions in human transplanted lungs. miR-21 showed a net overexpression in BOS lesions: it was primarily expressed in fibroblasts and in activated epithelial cells in all human BOS cases, while it was absent in normal lungs, thus clearly demonstrating upregulation in BOS; miR-34a was clearly expressed in BOS proliferating fibroblasts and in several non-inflammatory cell types, normal bronchiolar and alveolar epithelia and reactive pneumocytes. miR-21 expression in primary mesenchymal cell samples correlated with ISH results. The results we obtained open the possibility of identifying relevant key molecules involved in BOS which will be used as additional biomarkers and possible therapeutic targets and of gaining insight into the complex pathogenic network of this disease.