TRAIL-Dependent Resolution of Pulmonary Fibrosis

David M Habiel,Ana Paula Moreira,Nico Van Rooijen,Ana Lucia Coelho,Michael P Dunleavy,Ugur B Ismailoglu,Cory M Hogaboam,Karen A Cavassani

doi:10.1155/2018/7934362

Abstract

Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease characterized by the persistence of activated myofibroblasts resulting in excessive deposition of extracellular matrix proteins and profound tissue remodeling. In the present study, the expression of tumor necrosis factor- (TNF-) related apoptosis-inducing ligand (TRAIL) was key to the resolution of bleomycin-induced pulmonary fibrosis. Both in vivo and in vitro studies demonstrated that Gr-1+TRAIL+ bone marrow-derived myeloid cells blocked the activation of lung myofibroblasts. Although soluble TRAIL was increased in plasma from IPF patients, the presence of TRAIL+ myeloid cells was markedly reduced in IPF lung biopsies, and primary lung fibroblasts from this patient group expressed little of the TRAIL receptor-2 (DR5) when compared with appropriate normal samples. IL-13 was a potent inhibitor of DR5 expression in normal fibroblasts. Together, these results identified TRAIL+ myeloid cells as a critical mechanism in the resolution of pulmonary fibrosis, and strategies directed at promoting its function might have therapeutic potential in IPF.

Highlights

Idiopathic pulmonary fibrosis (IPF) is the most common clinical form of interstitial lung disease with a prognosis of median survival at 3–5 years after diagnosis and no effective pharmacological intervention [1,2,3]
Plasma TRAIL Concentration Is Increased in IPF Patients. These results suggested an important role for TRAIL+ myeloid cells in the resolution of experimental bleomycin-induced pulmonary fibrosis, it was unclear whether these findings had any relevance to clinical fibrotic lung disease
The expression of both TRAIL and its receptor was strongly decreased in normal lung fibroblasts exposed to IL-13 for 24 h (Figure 6(h)). These findings suggest that TRAIL is present in soluble form in IPF, there is a lack of TRAIL+ myeloid cells in IPF lung samples and IPF fibroblasts lack DR5 expression, presumably due, in part, to the inhibitory effects of IL-13

Summary

Introduction

IPF is the most common clinical form of interstitial lung disease with a prognosis of median survival at 3–5 years after diagnosis and no effective pharmacological intervention [1,2,3]. One strategy that has been reported to enhance TRAIL susceptibility in cancer involves altering the expression of this ligand on bone marrow-derived mesenchymal cells [17] These cells home to tumor sites and because of their regenerative capacity persist at these sites. The bone marrow is an important source of cells of both mesenchymal and hematopoietic origin which protect, regenerate, and restore the lung following fibrosis [18,19,20,21,22,23,24,25] The latter group of hematopoietic cells includes myeloid cells with potent immune regulatory properties, which are characterized by the concomitant surface expression of CD11b and Gr-1 in mice [26,27,28,29,30,31]

Methods

Results

Conclusion