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

• Published in: American journal of respiratory cell and molecular biology Vol. 49; no. 2; pp. 269 - 278
• Main Authors: Mathew, Biji, Jacobson, Jeffrey R, Siegler, Jessica H, Moitra, Jaideep, Blasco, Michael, Xie, Lishi, Unzueta, Crystal, Zhou, Tong, Evenoski, Carrie, Al-Sakka, Mohammed, Sharma, Rajesh, Huey, Ben, Bulent, Aydogan, Smith, Brett, Jayaraman, Sundararajan, Reddy, Narsa M, Reddy, Shekhar P, Fingerle-Rowson, Günter, Bucala, Richard, Dudek, Steven M, Natarajan, Viswanathan, Weichselbaum, Ralph R, Garcia, Joe G N
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.08.2013
• Subjects: Acute Lung Injury - genetics; Acute Lung Injury - metabolism; Acute Lung Injury - pathology; Acute Lung Injury - prevention & control; Aging - drug effects; Aging - genetics; Aging - metabolism; Aging - pathology; Aging - radiation effects; Animals; Bronchoalveolar Lavage Fluid; Cells, Cultured; Gamma Rays - adverse effects; Heme Oxygenase-1 - genetics; Heme Oxygenase-1 - metabolism; Humans; Hydrogen Peroxide - adverse effects; Hydrogen Peroxide - pharmacology; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - metabolism; Intramolecular Oxidoreductases - pharmacology; Macrophage Migration-Inhibitory Factors - genetics; Macrophage Migration-Inhibitory Factors - metabolism; Macrophage Migration-Inhibitory Factors - pharmacology; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; NAD(P)H Dehydrogenase (Quinone) - genetics; NAD(P)H Dehydrogenase (Quinone) - metabolism; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oxidants - adverse effects; Oxidants - pharmacology; Radiation Injuries, Experimental - genetics; Radiation Injuries, Experimental - metabolism; Radiation Injuries, Experimental - pathology; Radiation Injuries, Experimental - prevention & control
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2012-0291OC

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.