ResolvinD1 stimulates epithelial wound repair and inhibits TGF-β-induced EMT whilst reducing fibroproliferation and collagen production

Shengxing Zheng,Qian Wang,Vijay D'Souza,Dom Bartis,Rachel Dancer,Dhruv Parekh,Fang Gao,Qingquan Lian,Shengwei Jin,David R Thickett

doi:10.1038/labinvest.2017.114

Abstract

Acute and chronic inflammatory lung diseases are often associated with epithelial cell injury/loss and fibroproliferative responses. ResolvinD1 (RvD1) is biosynthesized during the resolution phase of inflammatory response and exerts potent anti-inflammatory and promotes resolution of inflammatory lung diseases. The aim of this study was to investigate whether RvD1 exerts protective effects on alveolar epithelial cell function/differentiation and protects against fibroproliferative stimuli. Primary human alveolar type II cells were used to model the effects of RvD1 in vitro upon wound repair, proliferation, apoptosis, transdifferentiation, and epithelial–mesenchymal transition (EMT). Effects of RvD1 upon primary human lung fibroblast proliferation, collagen production, and myofibroblast differentiation were also examined. RvD1 promoted alveolar type II (ATII) cell wound repair and proliferation. RvD1 protected ATII cells against sFas-ligand/TNF-α-induced apoptosis and inhibition on cell proliferation and viability. RvD1 promoted ATII cells transdifferentiation. Moreover, we demonstrate that RvD1 inhibited EMT in response to TGF-β. Furthermore RvD1 inhibited human lung fibroblast proliferation, collagen production, and myofibroblast differentiation induced by both TGF-β and bronchoalveolar lavage fluid from acute respiratory distress syndrome (ARDS) patients. The effects of RvD1 were PI3-kinase dependent and mediated via the resolvin receptor. RvD1 seems to promote alveolar epithelial repair by stimulating ATII cells wound repair, proliferation, reducing apoptosis, and inhibiting TGF-β-induced EMT. While RvD1 reduced fibroproliferation, collagen production, and myofibroblast differentiation. Together, these results suggest a potential new therapeutic strategy for preventing and treating chronic diseases (such as idiopathic pulmonary fibrosis) as well as the fibroproliferative phase of ARDS by targeting RvD1 actions that emphasizes natural resolution signaling pathways.

Highlights

Acute and chronic inflammatory lung diseases are often associated with epithelial cell injury/loss and fibroproliferative responses
Our results indicate that RvD1 promotes epithelial wound repair and inhibited TGF-β induced epithelial–mesenchymal transition (EMT) in human adult type II alveolar epithelial cells, whilst inhibiting fibroproliferation and reducing the effects of TGF-β on primary human lung fibroblast (HLF) collagen production and myofibroblast differentiation
acute respiratory distress syndrome (ARDS) bronchoalveolar lavage fluid (BALF) increased alveolar type II (ATII) cell wound closure compared with media control.[23]

Summary

Introduction

Acute and chronic inflammatory lung diseases are often associated with epithelial cell injury/loss and fibroproliferative responses. RvD1 seems to promote alveolar epithelial repair by stimulating ATII cells wound repair, proliferation, reducing apoptosis, and inhibiting TGF-β-induced EMT. While RvD1 reduced fibroproliferation, collagen production, and myofibroblast differentiation Together, these results suggest a potential new therapeutic strategy for preventing and treating chronic diseases (such as idiopathic pulmonary fibrosis) as well as the fibroproliferative phase of ARDS by targeting RvD1 actions that emphasizes natural resolution signaling pathways. In acute lung diseases such as acute respiratory distress syndrome (ARDS), the degree of the epithelial injury and the loss of alveolar epithelial cells due to Fas-ligand–mediated apoptosis is an important predictor of outcome.[11,12,13] In some cases of ARDS, a marked fibroproliferative response is associated with bad outcome.[14] a therapy that promotes epithelial repair and inhibits epithelial–mesenchymal transition (EMT). ResolvinD1 stimulates epithelial wound repair in HAECs S Zheng et al the lipoxinA4 receptor/formyl peptide receptor 2 (ALX/FPR2) with high affinity.[21]

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