Biochemical Pathway Seen for First Time to Play Role in Promoting Lung Fibrosis

A biochemical pathway in the lungs, in which an antioxidant called glutathione (GSH) binds to and changes the nature of specific proteins, may be involved in the development of pulmonary fibrosis, according to researchers at the University of Vermont.

The study, “Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase π,” published in JCI Insight, suggests that targeting the enzyme involved in this process may be an effective therapeutic approach for patients with idiopathic pulmonary fibrosis (IPF).

The causes of lung fibrosis are largely unknown, but studies have reported that exposure to certain agents, such as cigarette smoke, mineral dusts, and radiation, induce perturbations in the redox status and oxidative stress, ultimately leading to pulmonary fibrosis.

In the setting of such fibrosis, injury to the epithelial cells that line the lung airways is associated with exacerbated death of these cells and proliferation of fibroblasts that form the lung scarring. At the same time, specific factors are produced that further increase the fibrotic process, including the FAS protein.

GSH is an important antioxidant that has been described in IPF patients, particularly in its oxidized form. It can bind to specific amino acids in proteins, modifying their structure and function, through a process called glutathionylation that is mediated by the glutathione-S-transferase π (GSTP) enzyme. In a recent report, the researchers showed that FAS is one of the proteins that can bind with GSH, but how these alterations impact lung fibrosis was not understood.

Now, the team led by David H. McMillan studied the role of adding GSH to the FAS protein in IPF patients. Researchers found that these patients had high levels of the GSTP enzyme in the lungs, particularly in epithelial cells, and an increased interaction between GSTP and FAS.  

The team then developed two mice models of lung fibrosis (bleomycin and AdTGFβ), both genetically modified to lack the GSTP enzyme. Compared to mice expressing the enzyme, these mice had lower FAS glutathionylation and vascular remodelling.

Importantly, use of a GSTP inhibitor called TLK117 when the bleomycin-and AdTGFβ-induced fibrosis was already apparent also reduced vascular remodeling, epithelial cell death, FAS glutathionylation, and total protein glutathionylation. 

These finding suggest that GSTP inhibition may be a new therapeutic target for IPF patients or patients with other lung fibrotic diseases.

As the researchers concluded: “The current study points to the importance not of GSH per se, but a unique facet of GSH chemistry, which involves its covalent incorporation into proteins, catalyzed by GSTP, a biochemical pathway that has not previously been recognized in settings of pulmonary fibrosis. Thus, a clinical trial utilizing the GSTP inhibitor described herein in IPF patients appears well warranted, and may yield new insights into the functional importance of S-glutathionylation chemistry in the pathogenesis and progression of this deadly disease.”