Ozone (O3)-driven pulmonary inflammation is partly regulated by damage associated molecular patterns (DAMPs) binding to scavenging receptors (SRs). However, how SRs and DAMPs regulate O3-induced pulmonary inflammation remains incompletely understood. CD163 is a SR responsible for clearing cell free hemoglobin (CFH), a DAMP which accumulates during acute pulmonary injury and is associated with worsening respiratory outcomes. We hypothesized that increased CD163 is necessary for reducing CFH levels and resolving O3-induced pulmonary injury. To test this hypothesis, we defined CD163 and CFH responses to O3 exposure in C57BL/6N (WT) and CD163 deficient (Cd163-/-) mice, as well as in human bronchoalveolar lavage fluid (BALF). In WT mice, lung Cd163 expression was significantly increased by O3 during peak inflammation and declined 24 hours post exposure. Human exposure studies revealed a diversity of Cd163 expression and a reduction of CFH following O3 exposure, suggesting regulation of this pathway in humans. When compared to WT mice, Cd163-/- mice had augmented O3-induced pulmonary injury, inflammation, and oxidative stress. Further, the antioxidant EUK-134 did not reduce O3-induced pulmonary oxidative stress in Cd163-/- mice, suggesting a role for CD163 in the pulmonary response to oxidative insults. Furthermore, compared to WT controls, Cd163-/- mice receiving an oropharyngeal aspiration of CFH had a significant increase in airspace inflammation. Combined, these findings suggest that CD163 mediated clearance of CFH is involved in resolving O3-induced pulmonary injury, inflammation, and oxidative stress.
Cochran, S. J., Saunders, B., Schott, E., Dunigan-Russell, K., Hutton, G. M., Vose, A., Birukova, A., Rankin, C., McMahon, T. J., Zhu, H., Khramtsov, V. V., Velayutham, M., Hussain, S., Tighe, R. M., Gowdy, K. M.
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