Dysregulated micro-RNA expression in bronchiolitis obliterans syndrome post lung transplantation. From System Biology to validation by in situ hybridization.

BOS is characterized by fibrotic bronchiolar obliteration. MicroRNAs (miRs), are small, non-coding, single stranded RNAs playing a role in many biological processes including EMT. Recent studies demonstrated a role of miRs in fibrotic disorders but evidence on BOS are lacking. We applied an SB approach and computationally identified and scored a limited panel of miRs potentially relevant in BOS. All pathways involved in BOS were included, enhanced using the ReNEs software, then list of intronic miRs was extracted. The initial panel of 54 candidates was scored considering miR activity on pathways and previous validation. To validate SB analysis we selected, among miR with ValCov score >0.4, miR21 and miR34a that were assessed by ISH lung BOS grafts of orthotopic rat lung Tx model explanted human BOS lungs. Mir34a showed positivity in healthy control lungs whereas in pathologic lungs it didn't show any significant expression. A very high degree of miR21 was documented in OB lesions of the BOS lung, while normal human lung had minimal miR21 positivity. In addition, while native rat lung had no miR21 expression, a high degree of miR21 was documented in myofibroblasts of the OB lesion developed 15 days after Tx. Our SB approach is validated and recognizes miR21 and mir34a as a pathogenic factor and a possible therapeutic target in BOS.