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

Biji Mathew, Jeffrey R. Jacobson, Jessica H. Siegler, Jaideep Moitra, Michael Blasco, Lishi Xie, Crystal Unzueta, Tong Zhou, Carrie Evenoski, Mohammed Al-Sakka, Rajesh Sharma, Ben Huey, Aydogan Bulent, Brett Smith, Sundararajan Jayaraman, Narsa M. Reddy, Shekhar P. Reddy, Günter Fingerle-Rowson, Richard Bucala, Steven M. DudekViswanathan Natarajan, Ralph R. Weichselbaum, Joe G N Garcia

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


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 thatpolymorphisms inthegene(MIF) encodingmacrophage 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 exposedwild-type and genetically engineered mif-/- mice to 20 Gy single-fraction thoracic radiation to investigate the agerelated role ofMIF 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-typemice. 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 thenuclear expressionofNF-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 (H 2O2) 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 forMIF in radiation-induced changes in lung-cell antioxidant concentrations via Nrf2, and suggest that MIF may contribute to age-related susceptibility to thoracic radiation.

Original languageEnglish (US)
Pages (from-to)269-278
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Issue number2
StatePublished - Aug 2013


  • Aging
  • Antioxidant system
  • Lung vascular permeability
  • Macrophage migratory inhibition factor
  • Nrf2
  • Radiation pneumonitis

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology


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