Role of migratory inhibition factor in age-related susceptibility to radiation lung injury via NF-E2-related factor-2 and antioxidant regulation.

TitleRole of migratory inhibition factor in age-related susceptibility to radiation lung injury via NF-E2-related factor-2 and antioxidant regulation.
Publication TypeJournal Article
Year of Publication2013
AuthorsMathew B, Jacobson JR, Siegler JH, Moitra J, Blasco M, Xie L, Unzueta C, Zhou T, Evenoski C, Al-Sakka M, Sharma R, Huey B, Bulent A, Smith B, Jayaraman S, Reddy NM, Reddy SP, Fingerle-Rowson G, Bucala R, Dudek SM, Natarajan V, Weichselbaum RR, Garcia JGN
JournalAm J Respir Cell Mol Biol
Volume49
Issue2
Pagination269-78
Date Published2013 Aug
ISSN Number1535-4989
KeywordsAcute Lung Injury, Aging, Animals, Bronchoalveolar Lavage Fluid, Cells, Cultured, Gamma Rays, Heme Oxygenase-1, Humans, Hydrogen Peroxide, Intramolecular Oxidoreductases, Macrophage Migration-Inhibitory Factors, Membrane Proteins, Mice, Mice, Knockout, NAD(P)H Dehydrogenase (Quinone), NF-E2-Related Factor 2, Oxidants, Radiation Injuries, Experimental
Abstract

<p>Microvascular injury and increased vascular leakage are prominent features of radiation-induced lung injury (RILI), and often follow cancer-associated thoracic irradiation. Our previous studies demonstrated that polymorphisms in the gene (MIF) encoding macrophage migratory inhibition factor (MIF), a multifunctional pleiotropic cytokine, confer susceptibility to acute inflammatory lung injury and increased vascular permeability, particularly in senescent mice. In this study, we exposed wild-type and genetically engineered mif(-/-) mice to 20 Gy single-fraction thoracic radiation to investigate the age-related role of MIF in murine RILI (mice were aged 8 wk, 8 mo, or 16 mo). Relative to 8-week-old mice, decreased MIF was observed in bronchoalveolar lavage fluid and lung tissue of 8- to 16-month-old wild-type mice. In addition, radiated 8- to 16-month-old mif(-/-) mice exhibited significantly decreased bronchoalveolar lavage fluid total antioxidant concentrations with progressive age-related decreases in the nuclear expression of NF-E2-related factor-2 (Nrf2), a transcription factor involved in antioxidant gene up-regulation in response to reactive oxygen species. This was accompanied by decreases in both protein concentrations (NQO1, GCLC, and heme oxygenase-1) and mRNA concentrations (Gpx1, Prdx1, and Txn1) of Nrf2-influenced antioxidant gene targets. In addition, MIF-silenced (short, interfering RNA) human lung endothelial cells failed to express Nrf2 after oxidative (H2O2) challenge, an effect reversed by recombinant MIF administration. However, treatment with an antioxidant (glutathione reduced ester), but not an Nrf2 substrate (N-acetyl cysteine), protected aged mif(-/-) mice from RILI. These findings implicate an important role for MIF in radiation-induced changes in lung-cell antioxidant concentrations via Nrf2, and suggest that MIF may contribute to age-related susceptibility to thoracic radiation.</p>

DOI10.1165/rcmb.2012-0291OC
Alternate JournalAm. J. Respir. Cell Mol. Biol.
PubMed ID23526214
PubMed Central IDPMC3824032
Grant ListAI 42310 / AI / NIAID NIH HHS / United States
R56 AI042310 / AI / NIAID NIH HHS / United States
HL 58094 / HL / NHLBI NIH HHS / United States
P01 HL098050 / HL / NHLBI NIH HHS / United States
R01 AI042310 / AI / NIAID NIH HHS / United States