Transglutaminase 2: a novel therapeutic target for idiopathic pulmonary fibrosis using selective small molecule inhibitors

Shaun Fell,Zhuo Wang,Carmel Nanthakumar,Martin Griffin,Andy Blanchard

doi:10.1007/s00726-020-02938-w

Shaun Fell, Zhuo Wang + Show 3 more

Open Access

https://doi.org/10.1007/s00726-020-02938-w

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Journal: Amino acids	Publication Date: Jan 21, 2021
Citations: 17	License type: open-access

Affiliation: Aston University, Age UK

Abstract

This study investigates the effects of a site-directed TG2-selective inhibitor on the lung myofibroblast phenotype and ECM deposition to elucidate TG2 as a novel therapeutic target in idiopathic pulmonary fibrosis (IPF)—an incurable progressive fibrotic disease. IPF fibroblasts showed increased expression of TG2, α smooth muscle actin (αSMA) and fibronectin (FN) with increased extracellular TG2 and transforming growth factor β1 (TGFβ1) compared to normal human lung fibroblasts (NHLFs) which do not express αSMA and express lower levels of FN. The myofibroblast phenotype shown by IPF fibroblasts could be reversed by selective TG2 inhibition with a reduction in matrix FN and TGFβ1 deposition. TG2 transduction or TGFβ1 treatment of NHLFs led to a comparable phenotype to that of IPF fibroblasts which was reversible following selective TG2 inhibition. Addition of exogenous TG2 to NHLFs also induced the myofibroblast phenotype by a mechanism involving TGFβ1 activation which could be ameliorated by selective TG2 inhibition. SMAD3-deleted IPF fibroblasts via CRISPR-cas9 genome editing, showed reduced TG2 protein levels following TGFβ1 stimulation. This study demonstrates a key role for TG2 in the induction of the myofibroblast phenotype and shows the potential for TG2-selective inhibitors as therapeutic agents for the treatment of fibrotic lung diseases like IPF.

Highlights

Idiopathic pulmonary fibrosis (IPF) is an incurable and lifethreatening disease with a median survival rate of 2–3 years in the UK (Strongman et al 2018)
Transglutaminase 2 (TG2) was significantly upregulated in IPF fibroblasts, in comparison to normal human lung fibroblasts (NHLFs) (Fig. 1a and b) with IPF fibroblasts showing a significant increase in both FN and α smooth muscle actin, compared to NHLFs
Later studies have shown that increased expression of TG2 is found in the lungs of IPF patients and that TG2-KO mice develop significantly reduced bleomycin-induced fibrosis compared to wild-type mice (Olsen et al 2014)

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is an incurable and lifethreatening disease with a median survival rate of 2–3 years in the UK (Strongman et al 2018). Histological analysis of IPF samples show thick collagen and ‘fibroblast foci’ in areas of fibrosis (Kekevian et al 2014). (ECM) proteins above the rate of ECM degradation characterises IPF (Dragsbaek et al 2015; Ramos et al 2001). It has been demonstrated by Mora et al that there has been a high attrition rate for drugs that enter clinical trials for the treatment of IPF, and, this highlights the demand for promising new targets to be identified (Mora et al 2017)

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