The impact of Macrophage Migration Inhibitory Factor on Cigarette Induced Emphysematous Disease Severity

Cigarette smoke (CS) is the most common cause of chronic obstructive pulmonary diseases (COPD) including emphysema. Emphysema is a debilitating disease characterized by oxidative stress, apoptosis, and alveolar tissue loss. CS, which contains and enhances reactive oxygen species (ROS), impacts all cell types within the lung parenchyma and airways, causing alveolar tissue destruction through four mechanisms: 1) oxidative stress, 2) inflammation, 3) protease-induced degradation of the extracellular matrix, and 4) enhanced alveolar epithelial and endothelial cell (EndoC) apoptosis. Importantly, these mechanisms all cause apoptosis through intrinsic mitochondrial pathways or through extrinsic death receptor-mediated pathways. With emphysema progression, oxidative stress is continuously exacerbated in response to CS, contributing to enhanced apoptosis that by definition out paces repair processes. Recognizing that about a fifth of all smokers will develop emphysema, suggesting differential genetic susceptibilities, we focused on intrinsic modifiers of disease that may be altered by chronic CS exposure. Macrophage migration inhibitor factor (MIF), a pleiotropic cytokine with intrinsic oxidoreductase activity is one potential factor conferring cytoprotection from CS-induced damage. Studies in human pulmonary EndoC demonstrate that MIF antagonizes CS-induced apoptosis. Here we show for the first time that MIF is significantly reduced in patients with COPD. This is confirmed in our murine model of chronic CS exposure. The absence of MIF leads to enhanced CS-induced DNA damage, lung EndoC apoptosis, and exacerbated alveolar airspace enlargement. These results highlight a crucial role for MIF in antagonizing CS-induced toxicity in the lung and resultant emphysematous tissue remodeling by maintaining EndoC homeostasis. To further investigate the capacity and molecular mechanism(s) by which MIF modifies oxidant injury we aimed to understand the potential effect of MIF on xanthine oxidoreductase (XOR), a superoxide-generating enzyme that is increased in human COPD and mediates CS-induced DNA damage and EndoC apoptosis. Here we showed that superoxide concentrations are elevated following CS exposure in the absence of MIF. In addition this report demonstrates that XOR hyperactivation and apoptosis in the absence of MIF occurred via a p38 mitogen activated protein (MAP) kinase-dependent mechanism. This is the first report to show that MIF was sufficient to directly suppress ASK1 enzymatic activity, upstream of p38 activation, and providing one possible mechanism by which MIF suppresses CS-mediated cytotoxicity in the lung. We uncovered another potential and novel mechanism whereby MIF confers protection from oxidant injury, by positively regulating nuclear factor erythroid 2-related factor 2 (NRF2), a major regulator of the antioxidant (AO) response element (ARE). We demonstrated that the downstream targets of NRF2 are significantly decreased following CS exposure in MIF deficient animals. This report further links MIF to the stabilization of NRF2 through a mechanism involving c-Jun activation domain binding protein-1 (JAB1), a recognized intracellular receptor for MIF. Taken together, the results of this study provide strong support for a novel role for MIF as a determinant of emphysema disease severity in mouse and man, impacting on pulmonary EndoC and alveolar homeostasis, and regulating both oxidant and antioxidant production, that in the absence of MIF contribute to oxidative stress, cell damage, and apoptosis