title: Oxidative Modifications of Protein Tyrosyl Residues Are Increased in Plasma of Human Subjects with Interstitial Lung Disease.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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).
  
  
  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.
authors.affiliation: 1 Division of Nephrology.|Department of Internal Medicine, and 2 Computational Medicine and Biology, University of Michigan, Ann Arbor, Michigan; and.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.affiliation: 1 Division of Nephrology.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Vivekanandan-Giri
authors.affiliation: 3 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and.
authors.forename: Morgan L
authors.initials: ML
authors.lastname: Locy
authors.affiliation: 3 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and.
authors.forename: Tejaswini
authors.initials: T
authors.lastname: Kulkarni
authors.affiliation: 4 Department of Biostatistics, University of Alabama, Birmingham, Alabama.
authors.forename: Degui
authors.initials: D
authors.lastname: Zhi
authors.affiliation: 1 Division of Nephrology.
authors.forename: Lixia
authors.initials: L
authors.lastname: Zeng
authors.affiliation: 1 Division of Nephrology.
authors.forename: Jaeman
authors.initials: J
authors.lastname: Byun
authors.affiliation: 3 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and.
authors.forename: Joao A
authors.initials: JA
authors.lastname: de Andrade
authors.affiliation: 3 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, and.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018384:Oxidative Stress; D053719:Tandem Mass Spectrometry; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000097:blood
chemical_list: D015415:Biomarkers; C002744:3-nitrotyrosine; D014443:Tyrosine; C007543:dityrosine; C087259:3-chlorotyrosine
keywords: chlorotyrosine; dityrosine; mass spectrometry; nitrotyrosine; oxidative stress