Abstract

Microvascular injury and increased vascular leak are prominent features of radiation-induced lung injury (RILI) andoften follow cancer-associated thoracic irradiation.Our previous studies demonstrated that polymorphisms in the gene (MIF)encoding macrophage migratory inhibition factor (MIF), a multi-functional pleiotropic cytokine, confer susceptibility to acute inflammatory lung injury and increased vascular permeability. In this study, we exposed wildtype (WT) and genetically engineered mif-/-miceto 20 Gysingle fraction thoracic radiation to investigate the age-related role of MIF in a preclinical model of murine RILI (ages 8 wk, 8 mos, 16 mos). Relative to 8wk old mice,decreased MIF was observed in bronchoalveolar lavage (BAL)fluid and lung tissues of 8-16 mos wildtypemice.Additionally, radiated 8-16 mosmif-/-mice exhibit significantly decreased total antioxidant levelsin BAL with progressive age-related decreasesin nuclear expression of Nrf2, a transcription factor involved in antioxidant gene upregulation in response to reactive oxygen species. This was accompanied by decreasesin both protein levels (NQO1, GCLC, heme oxygenase-1) and mRNA levels (Gpx1, Prdx1,Txn1) of Nrf2-influenced antioxidant gene targets.Additionally, MIF-silenced (siRNA) human lung endothelial cells failed to express Nrf2 following oxidative (H2O2) challenge, an effect reversed byrecombinant MIF administration. However, treatment withan antioxidant (GSH) but not an Nrf2 substrate (NAC), protected aged mif-/-mice from RILI.These findings implicatean important role for MIFin radiation-induced alterations in lung cell antioxidant levels via Nrf2and suggest that MIF may contribute to age-related susceptibility to thoracic radiation.