Role of A2B adenosine receptor-dependent adenosine signaling in multi-walled carbon nanotube-triggered lung fibrosis in mice

Biying Liu,Zhigang Zhang,Siyu Li,Bing Han,Hao Wu,Ruiqi Baiyun,Jingjing Lu,Yueying Lv,Qizheng Bing,Xiaoya Zhang

doi:10.1186/s12951-019-0478-y

Abstract

BackgroundMulti-walled carbon nanotube (MWCNT)-induced lung fibrosis leads to health concerns in human. However, the mechanisms underlying fibrosis pathogenesis remains unclear. The adenosine (ADO) is produced in response to injury and serves a detrimental role in lung fibrosis. In this study, we aimed to explore the ADO signaling in the progression of lung fibrosis induced by MWCNT.ResultsMWCNT exposure markedly increased A2B adenosine receptor (A2BAR) expression in the lungs and ADO level in bronchoalveolar lavage fluid, combined with elevation of blood neutrophils, collagen fiber deposition, and activation of myeloperoxidase (MPO) activity in the lungs. Furthermore, MWCNT exposure elicited an activation of transforming growth factor (TGF)-β1 and follistatin-like 1 (Fstl1), leading to fibroblasts recruitment and differentiation into myofibroblasts in the lungs in an A2BAR-dependent manner. Conversely, treatment of the selective A2BAR antagonist CVT-6883 exhibited a significant reduction in levels of fibrosis mediators and efficiently decreased cytotoxicity and inflammatory in MWCNT treated mice.ConclusionOur results reveal that accumulation of extracellular ADO promotes the process of the fibroblast-to-myofibroblast transition via A2BAR/TGF-β1/Fstl1 signaling in MWCNT-induced lung fibrosis.

Highlights

Multi-walled carbon nanotube (MWCNT)-induced lung fibrosis leads to health concerns in human
Normalization of lung fibrosis in the lungs of CVT‐6883‐treated mice To further determine the effect of A 2BAR in the lung fibrosis of MWCNT exposure, we examined the protein level of two major extracellular matrix (ECM) proteins (collagen I and fibronectin 1 (FN1))
Our results showed that MWCNT remarkably stimulated the expression of transforming growth factor (TGF)-β1 and Smad3 phosphorylation in the lungs in an A2B adenosine receptor (A2BAR)-dependent manner

Summary

Introduction

Multi-walled carbon nanotube (MWCNT)-induced lung fibrosis leads to health concerns in human. We aimed to explore the ADO signaling in the progression of lung fibrosis induced by MWCNT. Because of the high demand for CNTs, it must be concerned that the health hazards of CNTs for human occupational and environmental exposure are more serious [2, 3]. MWCNTs deposit in the respiratory tract and increase lung burden, eventually leading to chronic inflammation and high risks of related adverse effects such as fibrosis [8]. The pathologic development and features of CNT-induced pulmonary interstitial fibrosis overlap with those of irreversible pulmonary fibrosis (IPF) and pneumoconiosis considerably. The fibrosis is progressive post-exposure and characterized by fibroblast

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