Xanthine Oxidase-Induced Vascular Dysfunction in Inhalation Toxicology

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Project Summary Exposure to titanium dioxide (TiO2) via inhalation is a considerable occupational healthcare issue as it results in not only in a local pulmonary inflammatory response but also mediates systemic vascular dysfunction. However, the signaling mechanisms underpinning the link between a primary inflammatory event in the lung with systemic vascular consequences are unclear; especially, if the toxicant remains localized primarily in the pulmonary tissue. One potential contributor to this process may be xanthine oxidoreductase (XOR), an enzyme that is upregulated under inflammatory conditions, can be released into the circulation and avidly bind to glycosaminoglycans (GAGs) on the endothelial surface and drive endothelial dysfunction via production of oxidants. We have recently demonstrated that a key source of circulating XOR is the liver whereby hepatocytes respond to inflammatory stimuli by releasing XOR to the circulation. This process seems to be specific to the liver as genetic ablation of hepatocellular XOR, in the context of inflammatory stimulus, significantly depletes circulating XOR levels in a manner absent of compensation by other organs/tissues. While the liver seems to play a master regulator role for controlling XOR levels in the circulation, the signaling from the primary off-site insult (lungs) to the hepatocyte remains undefined affirming the need for further exploration of this area. To this end, we provide preliminary data demonstrating a substantive increase in plasma XOR following inhalation exposure to TiO2 in a murine model. In addition, exposure to TiO2 results in endothelium-dependent dysfunction in both the middle cerebral artery and thoracic aorta that is restored by treatment with the XOR-specific inhibitor, febuxostat. Collectively, these data incentivize the hypothesis that inhalation of TiO2 mediates signaling from the lung to the liver upregulating XOR with subsequent release to the circulation where it contributes to vascular dysfunction. The following specific aims will test this hypothesis: 1) define XOR-mediated contributions to vascular dysfunction allied to inhalation of TiO2 and establish the liver as the source of amplified circulating XOR and 2) Identify the signaling from the lung to liver which mediates upregulation of XOR in response to TiO2 inhalation. Combined, these aims will establish a novel pathway whereby a primary insult to pulmonary tissue confers off-site upregulation of XOR and downstream vascular consequences. This is significant as XOR is targetable by FDA-approved compounds (febuxostat and allopurinol) whereas other sources of oxidants (e.g. mitochondria, NADPH oxidase, uncoupled eNOS etc.) contributory to vascular dysfunction are not and thus sets the stage for rapid translation of results to the clinic by off-target application.