Abstract
Epigenetic changes, including miRNAs deregulation, have been suggested to play a significant role in development of obliterative bronchiolitis (OB) in transplanted lungs. Many studies have tried to identify ideal candidate miRNAs and the downstream pathways implicated in the bronchiolar fibro-obliterative process. Several candidate miRNAs, previously indicated as possibly being associated with OB, were analyzed by combining the quantitative real time-polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH) of lung tissues of OB affected patients. Disease and OB-lesion-specific expression of miR-21-5p was confirmed and by computational analysis we were able to identify the network of genes most probably associated miR-21-5p in the context of OB fibrogenesis. Among all potentially associated genes, STAT3 had a very high probability score. Immunohistochemistry showed that STAT3/miR-21-5p were co-over expressed in OB lesions, thus, suggesting miR-21-5p could regulate STAT3 expression. However, miR-21-5p inhibition in cultures of bronchiolitis obliterans syndrome (BOS) derived myofibroblasts did not significantly affect STAT3 mRNA and protein expression levels. This study demonstrates the specificity of miR-21-5p over-expression in OB lesions and contributes to existing knowledge on the miR-21-5p downstream pathway. Activation of STAT3 is associated with miR-21-5p upregulation, however, STAT-3 network activation is most likely complex and miR-21-5p is not the sole regulator of STAT3.
Highlights
Lung transplantation (LTx) is an effective therapy for many end-stage lung diseases.Chronic lung allograft dysfunction (CLAD), continues to limit long-term survival and presents with two, frequently overlapping, major clinical phenotypes: bronchiolitis 4.0/).obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) [1]
In a preliminary study we identified, via computational analysis, a panel of candidate miRNAs that are possibly involved in bronchiolitis obliterans syndrome (BOS) pathogenesis, and scored them according to the probability of them being involved in the condition [11]
in situ hybridization (ISH) tests confirmed the results presented by Di Carlo et al, 2016 [11], on the expression of miR-21-5p (Figure 1a and Table 2) and miR-34a-5p (Figure 1b and Table 2) in transplanted lungs. miR-21-5p showed de novo intense expression in the fibroblasts of obliterative lesions and interstitial fibrosis; miR-34a-5p was diffusely expressed in several cell types of normal lung tissues as well as in obliterative bronchiolitis (OB) and interstitial fibrosis [11]
Summary
Lung transplantation (LTx) is an effective therapy for many end-stage lung diseases.Chronic lung allograft dysfunction (CLAD), continues to limit long-term survival and presents with two, frequently overlapping, major clinical phenotypes: bronchiolitis 4.0/).obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) [1]. Chronic lung allograft dysfunction (CLAD), continues to limit long-term survival and presents with two, frequently overlapping, major clinical phenotypes: bronchiolitis 4.0/). BOS accounts for roughly 70–80% of cases and represents the main cause of long-term morbidity and mortality. BOS is the result of an inflammatory and fibrotic process inducing the occlusion of small airways, but its pathogenesis has not been clarified yet [2]. The histologic correlate of BOS is obliterative bronchiolitis (OB), which consists of bronchiolar segmental submucosal fibrosis that causes total and irreversible occlusion of the airway lumina [3]. There is no effective treatment for CLAD and pharmacological therapy is often unsuccessful once functional impairment has developed. Studies aiming to clarify the mechanisms underlying OB development have suggested that, in addition to alloimmune and inflammatory phenomena centered in the small airways, microRNA (miRNA)
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