MiR-21 in Lung Transplant Recipients With Chronic Lung Allograft Dysfunction.

Naofumi Miyahara,Peter Jaksch,Alberto Benazzo,Viktoria Laszlo,Felicitas Oberndorfer,Balasz Döme,Konrad Hoetzenecker,Mir Ali Hoda,Akinori Iwasaki,Walter Klepetko

doi:10.3389/ti.2021.10184

Abstract

Background: Micro-RNA-21 (miR-21) is a post-translational regulator involved in epithelial-to-mesenchymal transition (EMT). Since EMT is thought to contribute to chronic lung allograft dysfunction (CLAD), we aimed to characterize miR-21 expression and distinct EMT markers in CLAD. Methods: Expression of miR-21, vimentin, Notch intracellular domain (NICD) and SMAD 2/3 was investigated in explanted CLAD lungs of patients who underwent retransplantation. Circulating miR-21 was determined in collected serum samples of CLAD and matched stable recipients. Results: The frequency of miR-21 expression was higher in restrictive allograft syndrome (RAS) than in bronchiolitis obliterans syndrome (BOS) specimens (86 vs 30%, p = 0.01); Vimentin, NICD and p-SMAD 2/3 were positive in 17 (100%), 12 (71%), and 7 (42%) BOS patients and in 7 (100%), 4 (57%) and 4 (57%) RAS cases, respectively. All four markers were negative in control tissue from donor lungs. RAS patients showed a significant increase in serum concentration of miR-21 over time as compared to stable recipients (p = 0.040). Conclusion: To the best of our knowledge this is the first study highlighting the role miR-21 in CLAD. Further studies are necessary to investigate the involvement of miR-21 in the pathogenesis of CLAD and its potential as a therapeutic target.

Highlights

Chronic lung allograft dysfunction (CLAD) represents the main cause of long-term morbidity and mortality after lung transplantation (LTx)
Significant efforts have been made to unravel the pathophysiology of CLAD, the main causative factors as well as therapeutic targets are still elusive
This study aimed to investigate the concomitant expression pattern of miR-21 and transcription factors involved in fibroproliferative processes both in tissue and serum of CLAD patients over time

Summary

Introduction

Chronic lung allograft dysfunction (CLAD) represents the main cause of long-term morbidity and mortality after lung transplantation (LTx). After an initial epithelial and endothelial injury, a series of immune and inflammatory stimuli trigger the activation of different profibrogenic processes [2]. These include activation of specific signaling pathways, activation of resident mesenchymal stromal cells and macrophages, proliferation of myofibroblasts, deposition of collagen by fibroblasts as well as epithelial-tomesenchymal transition (EMT) [3, 4]. MicroRNA-21 (miR21) is a post-translational regulator of several signaling pathways involved in EMT It is a central regulator of the TGF-β1/SMAD [5] and is highly expressed during the development of lung fibrosis [6]. Since EMT is thought to contribute to chronic lung allograft dysfunction (CLAD), we aimed to characterize miR-21 expression and distinct EMT markers in CLAD

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Discussion

Conclusion