Endothelin-1 Induces Mesothelial Mesenchymal Transition and Correlates with Pleural Fibrosis in Tuberculous Pleural Effusions.

Zhung-Han Wu,Chi-Li Chung,Jie-Heng Tsai,Wei-Lin Chen,Cheng-Ying Hsieh

doi:10.3390/jcm8040426

Abstract

Endothelin (ET)-1 is involved in various fibrotic diseases. However, its implication in pleural fibrosis remains unknown. We aimed to study the profibrotic role of ET-1 in tuberculous pleural effusion (TBPE). The pleural effusion ET-1 levels were measured among 68 patients including transudative pleural effusion (TPE, n = 12), parapneumonic pleural effusion (PPE, n = 20), and TBPE (n = 36) groups. Pleural fibrosis, defined as radiological residual pleural thickening (RPT) and shadowing, was measured at 12-month follow-up. Additionally, the effect of ET-1 on mesothelial mesenchymal transition (MMT) and extracellular matrix (ECM) producion in human pleural mesothelial cells (PMCs) was assessed. Our findings revealed that effusion ET-1 levels were significantly higher in TBPE than in TPE and PPE, and were markedly higher in TBPE patients with RPT >10 mm than those with RPT ≤10 mm. ET-1 levels correlated substantially with residual pleural shadowing and independently predicted RPT >10 mm in TBPE. In PMCs, ET-1 time-dependently induced MMT with upregulation of α-smooth muscle actin and downregulation of E-cadherin, and stimulated ECM production; furthermore, ET receptor antagonists effectively abrogated these effects. In conclusion, ET-1 induces MMT and ECM synthesis in human PMCs and correlates with pleural fibrosis in TBPE. This study confers a novel insight into the pathogenesis and potential therapies for fibrotic pleural diseases.

Highlights

Endothelin (ET)-1, initially identified as a potent vasoconstrictor, has been substantially implicated in the pathogenesis of inflammation and fibrosis of various organs [1]
The present study aims to assess the profibrotic role of ET-1 in tuberculous pleural effusion (TBPE) and to elucidate the effect of ET-1 on mesenchymal transition (MMT) in human pleural mesothelial cells (PMCs) in the underlying mechanisms
All patients with transudative PE (TPE) were diagnosed with congestive heart failure, and the PPE group consisted of 8 uncomplicated PPE and 12 complicated PPE

Summary

Introduction

Endothelin (ET)-1, initially identified as a potent vasoconstrictor, has been substantially implicated in the pathogenesis of inflammation and fibrosis of various organs [1]. In the context of lung diseases, plasma ET-1 levels were elevated in patients with acute respiratory distress syndrome [2], and endothelin blockers reduced lipopolysaccharide-induced lung inflammation in vivo [3]. Increased expression of ET-1 was observed in lung tissues from patients with idiopathic pulmonary fibrosis (IPF) [4], and ET-1 was reported to recruit and differentiate lung fibroblasts into myofibroblasts, induce alveolar epithelial mesenchymal transition (EMT), and promote extracellular matrix (ECM) production [5,6,7]. TBPE remains the most common cause of pleural fibrosis where tuberculosis is endemic. Around 20–50% of patients with TBPE developed clinically significant pleural fibrosis of which the pathogenesis and management remain to be clarified [9,10]

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