Role of Migratory Inhibition Factor in Age-Related Susceptibility to Radiation Lung Injury via NF-E2–Related Factor–2 and Antioxidant Regulation

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 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 2/2 mice to 20 Gy single-fraction thoracic radiation to investigate the agerelated 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 2/2 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 (H 2 O 2 ) 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 2/2 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.

Endothelial CD74 mediates macrophage migration inhibitory factor protection in hyperoxic lung injury

“…Most recently, CD74 has been demonstrated in endothelial cells of patients with pulmonary HTN (43,44). Although the protective effect of MIF in endothelial cells has been described previously, the involvement of CD74 and its inducible expression as a consequence of hyperoxia are novel observations (6,22). An important limitation of this study is the lack of a mouse-specific monoclonal antibody that targets cell surface CD74.…”

“…One possibility is that this protection is mediated through increased antioxidant gene expression. Interestingly, a recent publication has suggested that silencing of MIF resulted in decreased NRF-2 activation, and hence, MIF would induce protection from oxidative stress-mediated damage (6). Multiple studies suggest that MIF provides protection from genotoxic stress and interferes with p53 and E2F-Rb signaling (19,60,61).…”

“…In the lung, CD74 expression has been reported in macrophages, type II pneumocytes, and upon oncogenic transformation (6,21,22). We hypothesized that constitutive or inducible CD74 expression is essential for MIF's protective effect in the lung.…”

“…In the lung, the mechanism for this protection remains poorly understood (4)(5)(6)(7). MIF is a pleiotropic cytokine that exists in preformed cytoplasmic pools in alveolar epithelial, alveolar endothelial, and pulmonary macrophages.…”

“…Multiple studies have linked functional polymorphisms in MIF to pulmonary disease, yet the effects of MIF polymorphisms in ARDS remain uncertain (13). Recently, investigations have suggested that MIF can protect against various forms of oxidative stress in the lung, including cigarette smoke and radiation (4)(5)(6)(7)14). Collectively, these observations suggest that whereas MIF secretion may correlate with disease severity, it may have a role in lung protection from oxidant injury.…”