Researchers in Switzerland identified di-tyrosine (DT) as a histological marker of idiopathic pulmonary fibrosis (IPF). The gene NOX4, which encodes the NADPH oxidase 4 enzyme, can generate enough H2O2 for the formation of DT in vitro, according to the study published in Antioxidants.

“Our study opens a number of important questions for further investigation including the timing of DT formation in IPF lungs, the types of [extracellular matrix] proteins undergoing DT formation, the alternative sources of H2O2, and the necessary heme-containing peroxidases leading to high DT in IPF,” the researchers wrote.

“Exploration of these questions might lead to the discovery of novel therapeutics for IPF and potentially other fibrotic diseases.”

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Even though it is known that oxidative damage is the main feature of IPF, the source of these oxidants and the consequences of their generation in the lungs are not well understood. 

Read more about IPF etiology

To investigate the link between NOX4 and DT, the team from the University of Geneva in Switzerland conducted immunohistochemical staining for DT and NOX4 in lung tissue obtained from patients with IPF and controls.

They found that in healthy lungs, DT was almost not detected. NOX4 was mostly present in normal vascular endothelium. However, in IPF lungs, both DT and NOX4 were found in several cell types. These included vascular smooth muscle cells, bronchial cells, and epithelial cells type 2.

The researchers then conducted a series of experiments to better address the link between these 2 markers. They grew human fibroblasts that had a mutation in the CYBA gene and therefore had reduced NOX4 activity.

They then induced NOX4 using transforming growth factor-beta 1. Even though this led to moderate DT staining after the addition of a heme-containing peroxidase in control cells, it did not lead to the same result in NOX4– deficient cells.

The researchers concluded that NOX4 promotes the formation of DT and that DT is a marker of IPF.


Blaskovic S, Donati Y, Ruchonnet-Metrailler I, et al. Di-tyrosine crosslinking and NOX4 expression as oxidative pathological markers in the lungs of patients with idiopathic pulmonary fibrosis. Antioxidants. 2021;18;10(11):1833. doi:10.3390/antiox10111833