Oxidative Modifications of Protein Tyrosyl Residues Are Increased in Plasma of Human Subjects with Interstitial Lung Disease.

Mon, 2016-08-22 14:30 -- voskuhlt
TitleOxidative Modifications of Protein Tyrosyl Residues Are Increased in Plasma of Human Subjects with Interstitial Lung Disease.
Publication TypeJournal Article
Year of Publication2016
AuthorsPennathur S, Vivekanandan-Giri A, Locy ML, Kulkarni T, Zhi D, Zeng L, Byun J, de Andrade JA, Thannickal VJ
JournalAm J Respir Crit Care Med
Volume193
Issue8
Pagination861-8
Date Published2016 Apr 15
ISSN1535-4970
Abstract

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 compared 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 in cellular models, a mouse model of injury-induced fibrosis, and in plasma of healthy control subjects and patients with ILD (n = 42 in each group).MEASUREMENTS AND MAIN RESULTS: Plasma levels of 3-chlorotyrosine, 3-nitrotyrosine, and o,o'-dityrosine were markedly elevated in patients with ILD compared with control subjects with receiver operating characteristic 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 sources of reactive oxygen species in the generation of these oxidized products.CONCLUSIONS: We demonstrate an increase in oxidized tyrosine moieties within proteins in the circulating plasma of patients with ILD. 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.

DOI10.1164/rccm.201505-0992OC
Alternate JournalAm. J. Respir. Crit. Care Med.
PubMed ID26575972
PubMed Central IDPMC4849179
Grant ListP01 HL114470 / HL / NHLBI NIH HHS / United States
P01 HL114470 / HL / NHLBI NIH HHS / United States
P30 DK89503 / DK / NIDDK NIH HHS / United States
R01 AG046210 / AG / NIA NIH HHS / United States
R01 HL094230 / HL / NHLBI NIH HHS / United States
U24 DK097153 / DK / NIDDK NIH HHS / United States
U24 DK097153 / DK / NIDDK NIH HHS / United States