Accumulation of isolevuglandin-modified protein in normal and fibrotic lung

AUTHORS

Mont SStacey , Davies SSSean S , Roberts Second LJL Jackson , Mernaugh RLRaymond L , McDonald WHW Hayes , Segal BHBrahm H , Zackert WWilliam , Kropski JAJonathan A , Blackwell TSTimothy S , Sekhar KRKonjeti R , Galligan JJJames J , Massion PPPierre P , Marnett LJLawrence J , Travis ELElizabeth L , Freeman MLMichael L . Scientific reports. 2016 4 27; 6(). 24919

PMID: 27118599[PubMed].
PMCID: PMC4847119.

ABSTRACT

Protein lysine modification by γ-ketoaldehyde isomers derived from arachidonic acid, termed isolevuglandins (IsoLGs), is emerging as a mechanistic link between pathogenic reactive oxygen species and disease progression. However, the questions of whether covalent modification of proteins by IsoLGs are subject to genetic regulation and the identity of IsoLG-modified proteins remain unclear. Herein we show that Nrf2 and Nox2 are key regulators of IsoLG modification in pulmonary tissue and report on the identity of proteins analyzed by LC-MS following immunoaffinity purification of IsoLG-modified proteins. Gene ontology analysis revealed that proteins in numerous cellular pathways are susceptible to IsoLG modification. Although cells tolerate basal levels of modification, exceeding them induces apoptosis. We found prominent modification in a murine model of radiation-induced pulmonary fibrosis and in idiopathic pulmonary fibrosis, two diseases considered to be promoted by gene-regulated oxidant stress. Based on these results we hypothesize that IsoLG modification is a hitherto unrecognized sequelae that contributes to radiation-induced pulmonary injury and IPF.