Isoketals (IsoKs) – highly reactive compounds formed when membrane lipids are attacked by free radicals – are emerging as a mechanistic link between pathogenic reactive oxygen species and disease progression. However, the identity of IsoK-modified proteins and whether isoketal generation is subject to genetic regulation remains unclear.
Stacey Mont, Michael L. Freeman, Ph.D., and colleagues found that the enzyme Nox2, which generates superoxide, and Nrf2-mediated antioxidant gene expression are key regulators of isoketals generated in pulmonary tissue.
Purification of IsoK-modified proteins followed by chromatography-mass spectrometry analysis revealed that proteins in numerous cellular pathways are susceptible to isoketal modification. Prominent modification occurred in a mouse model of radiation-induced pulmonary fibrosis and in human idiopathic pulmonary fibrosis. Modification inhibits protein degradation, which can induce programmed cell death (apoptosis).
These findings, published in Scientific Reports, identify isoketal-modified proteins as a previously unrecognized feature of pulmonary fibrosis and as a potential therapeutic target for this currently untreatable disease.
This research was supported in part by grants from the National Institutes of Health(HL112286, AI067798, CA068485).