TY - JOUR
T1 - Role of migratory inhibition factor in age-related susceptibility to radiation lung injury via NF-E2-related factor-2 and antioxidant regulation
AU - Mathew, Biji
AU - Jacobson, Jeffrey R.
AU - Siegler, Jessica H.
AU - Moitra, Jaideep
AU - Blasco, Michael
AU - Xie, Lishi
AU - Unzueta, Crystal
AU - Zhou, Tong
AU - Evenoski, Carrie
AU - Al-Sakka, Mohammed
AU - Sharma, Rajesh
AU - Huey, Ben
AU - Bulent, Aydogan
AU - Smith, Brett
AU - Jayaraman, Sundararajan
AU - Reddy, Narsa M.
AU - Reddy, Shekhar P.
AU - Fingerle-Rowson, Günter
AU - Bucala, Richard
AU - Dudek, Steven M.
AU - Natarajan, Viswanathan
AU - Weichselbaum, Ralph R.
AU - Garcia, Joe G.N.
PY - 2013/8
Y1 - 2013/8
N2 - 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.
AB - 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.
KW - Aging
KW - Antioxidant system
KW - Lung vascular permeability
KW - Macrophage migratory inhibition factor
KW - Nrf2
KW - Radiation pneumonitis
UR - http://www.scopus.com/inward/record.url?scp=84883185280&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84883185280&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2012-0291OC
DO - 10.1165/rcmb.2012-0291OC
M3 - Article
C2 - 23526214
AN - SCOPUS:84883185280
SN - 1044-1549
VL - 49
SP - 269
EP - 278
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 2
ER -