Pulmonary Fibrosis

RATIONALE:

Interstitial lung diseases (ILDs) are associated with oxidative stress. Plasma biomarkers that are directly linked to oxidative stress responses in this disease have not been identified. Stable oxidation products of tyrosine residues in proteins may reflect the oxidative microenvironment in the lung or a systemic inflammatory state.

OBJECTIVES:

To determine if levels of protein tyrosine oxidation are elevated in plasma of patients with ILD in comparison with an age- and sex-matched healthy control cohort.

METHODS:

Three tyrosine oxidation products, 3-chlorotyrosine, 3-nitrotyrosine, and o,o'-dityrosine, were quantified by tandem mass-spectrometry (MS/MS) in cellular models, a mouse model of injury-induced fibrosis, and in plasma of healthy controls and ILD patients (n = 42 in each group).

MEASUREMENTS AND MAIN RESULTS:

Plasma levels of 3-chlorotyrosine, 3-nitrotyrosine and o,o'-dityrosine were markedly elevated in ILD patients compared with control subjects with ROC curves separating these groups of 0.872, 0.893 and 0.997, respectively. In a murine model of lung fibrosis, levels of all three oxidative tyrosine modifications were increased in plasma and lung tissue. Cellular models support a critical role for a heme peroxidase and enzymatic source(s) of reactive oxygen species (ROS) in the generation of these oxidized products.

CONCLUSIONS:

We demonstrate an increase in oxidized tyrosine moieties within proteins in the circulating plasma of ILD patients. These data support the potential for development of oxidative stress-related biomarkers in early diagnosis, prognostication, and/or in evaluating responsiveness to emerging therapies for ILD.