title: Role of migratory inhibition factor in age-related susceptibility to radiation lung injury via NF-E2-related factor-2 and antioxidant regulation.
abstract: 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.
authors.affiliation: Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, IL 60612-7227, USA.
authors.forename: Biji
authors.initials: B
authors.lastname: Mathew
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jacobson
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Siegler
authors.forename: Jaideep
authors.initials: J
authors.lastname: Moitra
authors.forename: Michael
authors.initials: M
authors.lastname: Blasco
authors.forename: Lishi
authors.initials: L
authors.lastname: Xie
authors.forename: Crystal
authors.initials: C
authors.lastname: Unzueta
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.forename: Carrie
authors.initials: C
authors.lastname: Evenoski
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Sakka
authors.forename: Rajesh
authors.initials: R
authors.lastname: Sharma
authors.forename: Ben
authors.initials: B
authors.lastname: Huey
authors.forename: Aydogan
authors.initials: A
authors.lastname: Bulent
authors.forename: Brett
authors.initials: B
authors.lastname: Smith
authors.forename: Sundararajan
authors.initials: S
authors.lastname: Jayaraman
authors.forename: Narsa M
authors.initials: NM
authors.lastname: Reddy
authors.forename: Shekhar P
authors.initials: SP
authors.lastname: Reddy
authors.forename: Günter
authors.initials: G
authors.lastname: Fingerle-Rowson
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dudek
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Ralph R
authors.initials: RR
authors.lastname: Weichselbaum
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D000375:Aging / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002478:Cells, Cultured; D005720:Gamma Rays / Q000009:adverse effects*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000009:adverse effects / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000009:adverse effects / Q000494:pharmacology; D011833:Radiation Injuries, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D016877:Oxidants; D006861:Hydrogen Peroxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C491732:Nqo1 protein, mouse; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human; C076231:Mif protein, mouse