scholarly journals Blocking LOXL2 and TGFβ1 signalling induces collagen I turnover in precision-cut lung slices derived from patients with idiopathic pulmonary fibrosis

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-215745 ◽  
Author(s):  
Ying Wei ◽  
Wenting Dong ◽  
Julia Jackson ◽  
Tsung-Che Ho ◽  
Claude Jourdan Le Saux ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Lysyl Oxidase ◽  
Epigallocatechin Gallate ◽  
Transforming Growth Factor Β1 ◽  
Collagen I ◽  
Dual Inhibitor ◽  
Collagen Accumulation ◽  
Precision Cut Lung Slices

We recently identified epigallocatechin gallate (EGCG), a trihydroxyphenolic compound, as a dual inhibitor of lysyl oxidase-like2 and transforming growth factor-β1 (TGFβ1) receptor kinase that when given orally to patients with idiopathic pulmonary fibrosis (IPF) reversed profibrotic biomarkers in their diagnostic biopsies. Here, we extend these findings to advanced pulmonary fibrosis using cultured precision-cut lung slices from explants of patients with IPF undergoing transplantation. During these experiments, we were surprised to discover that not only did EGCG attenuate TGFβ1 signalling and new collagen accumulation but also activated matrix metalloproteinase-dependent collagen I turnover, raising the possibility of slow fibrosis resolution with continued treatment.

scholarly journals Greater cellular stiffness in fibroblasts from patients with idiopathic pulmonary fibrosis

2018 ◽  
Vol 315 (1) ◽  
pp. L59-L65 ◽  
Author(s):  
Jade Jaffar ◽  
Soung-Hee Yang ◽  
Sally Yunsun Kim ◽  
Hae-Won Kim ◽  
Alen Faiz ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Cellular Level ◽  
Lung Fibroblasts ◽  
Fibrotic Disease ◽  
Force Microscopy ◽  
Atomic Force ◽  
Organ Tissue

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease involving degenerative breathing capacity. Fibrotic disease is driven by dysregulation in mechanical forces at the organ, tissue, and cellular level. While it is known that, in certain pathologies, diseased cells are stiffer than healthy cells, it is not known if fibroblasts derived from patients with IPF are stiffer than their normal counterparts. Using IPF patient-derived cell cultures, we measured the stiffness of individual lung fibroblasts via high-resolution force maps using atomic force microscopy. Fibroblasts from patients with IPF were stiffer and had an augmented cytoskeletal response to transforming growth factor-β1 compared with fibroblasts from donors without IPF. The results from this novel study indicate that the increased stiffness of lung fibroblasts of IPF patients may contribute to the increased rigidity of fibrotic lung tissue.

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

Amino Acids ◽  
2021 ◽  
Author(s):  
Shaun Fell ◽  
Zhuo Wang ◽  
Andy Blanchard ◽  
Carmel Nanthakumar ◽  
Martin Griffin
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Therapeutic Target ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transglutaminase 2 ◽  
Transforming Growth Factor Β1 ◽  
Lung Fibroblasts ◽  
Myofibroblast Phenotype ◽  
Novel Therapeutic

AbstractThis 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.

Quantifying Plasma Levels of Transforming Growth Factor β1 in Idiopathic Pulmonary Fibrosis

2006 ◽  
Vol 42 (8) ◽  
pp. 380-383 ◽  
Author(s):  
María Molina-Molina ◽  
Sergio Lario ◽  
Patricio Luburich ◽  
José Ramírez ◽  
María Teresa Carrión ◽  
...  
Keyword(s):  
Growth Factor ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Plasma Levels ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1

scholarly journals Transforming growth factor β1 (TGFβ1)-induced CD44V6-NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis

2017 ◽  
Vol 292 (25) ◽  
pp. 10490-10519 ◽  
Author(s):  
Shibnath Ghatak ◽  
Vincent C. Hascall ◽  
Roger R. Markwald ◽  
Carol Feghali-Bostwick ◽  
Carol M. Artlett ◽  
...  
Keyword(s):  
Growth Factor ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1
Sign in / Sign up

Export Citation Format

Share Document