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. Dudek & 3 others Viswanathan Natarajan, Ralph R. Weichselbaum, Joe GN Garcia

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 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
Volume49
Issue number2
DOIs
StatePublished - Aug 2013
Externally publishedYes

Fingerprint

NF-E2-Related Factor 2
Radiation Injuries
Age Factors
Lung Injury
Antioxidants
Radiation
Thorax
Bronchoalveolar Lavage Fluid
Lung
Genes
Acetylcysteine
Heme Oxygenase-1
Fluids
Acute Lung Injury
Vascular System Injuries
Endothelial cells
Capillary Permeability
Small Interfering RNA
Glutathione
Cysteine

Keywords

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

ASJC Scopus subject areas

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

Cite this

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

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 49, No. 2, 08.2013, p. 269-278.

Research output: Contribution to journalArticle

Mathew, 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 2013, 'Role of migratory inhibition factor in age-related susceptibility to radiation lung injury via NF-E2-related factor-2 and antioxidant regulation', American Journal of Respiratory Cell and Molecular Biology, vol. 49, no. 2, pp. 269-278. https://doi.org/10.1165/rcmb.2012-0291OC
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 GN. / Role of migratory inhibition factor in age-related susceptibility to radiation lung injury via NF-E2-related factor-2 and antioxidant regulation. In: American Journal of Respiratory Cell and Molecular Biology. 2013 ; Vol. 49, No. 2. pp. 269-278.
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