CD163 protects against pulmonary injury and inflammation induced by acute O 3 exposure

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Abstract
Ozone (O 3 )-driven pulmonary inflammation is partly regulated by damage associated molecular patterns (DAMPs) binding to scavenging receptors (SRs). However, how SRs and DAMPs regulate O 3 -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 O 3 -induced pulmonary injury. To test this hypothesis, we defined CD163 and CFH responses to O 3 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 O 3 during peak inflammation and declined 24 hours post exposure. Human exposure studies revealed a diversity of Cd163 expression and a reduction of CFH following O 3 exposure, suggesting regulation of this pathway in humans. When compared to WT mice, Cd163 -/- mice had augmented O 3 -induced pulmonary injury, inflammation, and oxidative stress. Further, the antioxidant EUK-134 did not reduce O 3 -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 O 3 -induced pulmonary injury, inflammation, and oxidative stress. New & Noteworthy: Ozone (O 3 ) is known to induce damage associated molecular patterns (DAMPs) which drive lung inflammation. The scavenging receptor, CD163, binds and clears the DAMP cell free hemoglobin (CFH), which accumulates during sterile lung injury. Our findings indicate that O 3 exposure alters CD163 expression in the lung and that mice lacking Cd163 expression have more lung inflammation. Our data indicate that CD163 serves a protective role in response to acute O 3 exposure perhaps through CFH clearance.

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