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  • Glenn Hearson

Understanding the mechanisms of idiopathic pulmonary fibrosis in order to develop new treatments

Updated: Feb 21, 2023

IPF is a progressive and devastating lung disorder characterised by irreversible scarring (fibrosis) of the lung. IPF affects over 8,000 people in the UK. It causes disabling breathlessness, and often leads to death within a few years.

The cause of the disease is unknown despite much research and the few treatment options currently available do not stop the disease progression. One cell type in the lung termed myofibroblasts are the major cells responsible for the scar formation in IPF lung because their numbers are markedly increased and they secrete excessive amounts of extracellular molecules to directly cause lung scarring.

Myofibroblasts can be formed from normal fibroblasts (another cell type) through activation by the potent pro-fibrotic mediator termed transforming growth factor beta1 (TGFbeta1). Under normal conditions, the formation of myofibroblasts is inhibited by antifibrotic mediators. However, during the process of myofibroblast formation in IPF, the cells gradually lose the capability to produce antifibrotic mediators because the genes controlling these mediator production are switched off, resulting in myofibroblast accumulation, unopposed and excessive fibroblast growth and scar formation.

Genes are DNA regions encoding functional protein products. DNA is wrapped around a group of proteins called histones. Different molecular "tags" can stick onto different locations on histones and have different effects. Some “tags” in some locations are responsible for switching on the genes in that region. Other “tags” in other locations do the opposite.

Histone acetylation (addition of acetyl groups) is such a “tag” that switches on genes. Histone “tags” are reversible and can be targeted to keep the good genes switched on and the bad genes switched off.

Latest cellular studies indicate that abnormal histone tagging in the regions of antifibrotic genes is responsible for the switching off of these antifibrotic genes in lung fibroblasts, resulting in unopposed activation and proliferation of the cells and lung scarring in IPF.

By comparing normal lung fibroblasts with those from IPF patients and establishing different models of lung fibrosis, we intend to understand what histone “tags” are responsible for the switching off of antifibrotic genes, how they are added to histones, how to remove them, and if removing them can restore the expression of antifibrotic genes and reduce the accumulation of myofibroblasts and their production of the scar-causing molecules in IPF.

It is hopeful that the outcome of our research can lead to improved understanding of the mechanisms of IPF and new approaches targeting antifibrotic gene histone “tags” for IPF therapy.

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