Impact of mir21 Expression in Chronic Lung Allograft Dysfunction after Lung Transplantation

Abstract

Purpose Long-term survival after lung transplantation is still limited by the development of chronic lung allograft dysfunction (CLAD), presenting either as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS). Epithelial-to-mesenchymal transition (EMT) is recognized as one of the pathogenic processes contributing to CLAD. MiR-21 is a post-translational regulator of several pathways of fibrosis and has recently been related to EMT. In this study we aimed to characterize miR-21 expression and other markers of EMT in lung tissue of BOS and RAS patients. Methods Formalin-fixed paraffin-embedded tissue of 17 BOS patients and 7 RAS patients undergoing a lung retransplantation due to CLAD and 5 normal lung tissue samples (control) were evaluated for the expression following markers: vimentin, notch intracellular domain (NICD), p-SMAD 2/3, β-catenin, and E-cadherin. Slides were additionally stained for miR-21 by in situ hybridization (ISH). Expression of respective markers were graded in a semi-quantified manner by two blinded pathologists. Results Vimentin, NICD, p-SMAD 2/3 were positive in 13 (77%), 12 (71%), and 7 (42%) BOS patients, and in 5 (71%), 4 (57%) and 4 (57%) RAS patients, respectively. In contrast, β-catenin and E-cadherin staining were consistently negative in both groups. In comparision, no significant difference was found between BOS and RAS regarding these markers. MiR-21 expression was positive in 5 (30%) BOS cases and 6 (86%) RAS cases. The rate of miR-21 expression was significantly higher in RAS than in BOS (p=0.01). MiR-21 expression was associated with significant shorter freedom to BOS (11.5 vs 46.0 months, p=0.001, Figure 1), but had no impact on the development of RAS. Conclusion This first preliminary study could identify miR-21 as a possible biomarker and therapeutic target of CLAD and mirR-21 expression was related to worse outcomes in BOS cases. Further research is necessary to validate these findings in a larger cohort of patients.