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Immunol Lett. 2015 Jun;165(2):90-101. doi: 10.1016/j.imlet.2015.04.003. Epub 2015 Apr 27.

The mannose-6-phosphate analogue, PXS64, inhibits fibrosis via TGF-β1 pathway in human lung fibroblasts.

Author information

1
Drug Discovery, Pharmaxis, Australia. Electronic address: heidi.schilter@pharmaxis.com.au.
2
Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, USA.
3
Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria; Institute of Molecular Biology, Slovak Academy of Sciences, Slovak Republic.
4
Molecular Immunology Unit, Institute for Hygiene and Applied Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria.
5
Drug Discovery, Pharmaxis, Australia.
6
Australian Proteome Analysis Facility, Macquarie University, Australia.
7
Drug Discovery, Pharmaxis, Australia; School of Medical & Molecular Biosciences, University of Technology Sydney, Australia.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterised by a progressive decline in lung function which can be attributed to excessive scarring, inflammation and airway remodelling. Mannose-6-phosphate (M6P) is a strong inhibitor of fibrosis and its administration has been associated with beneficial effects in tendon repair surgery as well as nerve repair after injury. Given this promising therapeutic approach we developed an improved analogue of M6P, namely PXS64, and explored its anti-fibrotic effects in vitro. Normal human lung fibroblasts (NHLF) and human lung fibroblast 19 cells (HF19) were exposed to active recombinant human TGF-β1 to induce increases in fibrotic markers. rhTGF-β1 increased constitutive protein levels of fibronectin and collagen in the NHLF cells, whereas HF19 cells showed increased levels of fibronectin, collagen as well as αSMA (alpha smooth muscle actin). PXS64 demonstrated a robust inhibitory effect on all proteins analysed. IPF patient fibroblasts treated with PXS64 presented an improved phenotype in terms of their morphological appearance, as well as a decrease in fibrotic markers (collagen, CTGF, TGF-β3, tenascin C, αSMA and THBS1). To explore the cell signalling pathways involved in the anti-fibrotic effects of PXS64, proteomics analysis with iTRAQ labelling was performed and the data demonstrated a specific antagonistic effect on the TGF-β1 pathway. This study shows that PXS64 effectively inhibits the production of extracellular matrix, as well as myofibroblast differentiation during fibrosis. These results suggest that PXS64 influences tissue remodelling by inhibiting TGF-β1 signalling in NHLF and HF19 cell lines, as well as in IPF patient fibroblasts. Thus PXS64 is a potential candidate for preclinical application in pulmonary fibrosis.

KEYWORDS:

Fibroblasts; Idiopathic pulmonary fibrosis; M6P; Mannose-6-phosphate; PXS64; TGF-β1

PMID:
25929803
DOI:
10.1016/j.imlet.2015.04.003
[Indexed for MEDLINE]
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