Abstract
Prolonged exposure to hyperoxia has deleterious effects on the lung, provoking both inflammation and alveolar injury. The elements of hyperoxic injury, which result in high rates of lethality in experimental models, are thought to include multicellular immune responses. To characterize these alterations in immune cell populations, we performed time-of-flight mass cytometry (CyTOF) analysis of CD45-expressing immune cells in whole lung parenchyma and the bronchoalveolar space of mice, exposed to 48 hours of hyperoxia together with normoxic controls. At the tested time point, hyperoxia exposure resulted in decreased abundance of immunoregulatory populations (regulatory B cells, myeloid regulatory cells) in lung parenchyma and markedly decreased proliferation rates of myeloid regulatory cells, monocytes and alveolar macrophages. Additionally, hyperoxia caused a shift in the phenotype of alveolar macrophages, increasing proportion of cells with elevated CD68, CD44, CD11c, PD-L1, and CD205 expression levels. These changes occurred in the absence of histologically evident alveolar damage and abundance of neutrophils in the parenchyma or alveolar space did not change at these time points. Collectively, these findings demonstrate that pulmonary response to hyperoxia involves marked changes in specific subsets of myeloid and lymphoid populations. These findings have important implications for therapeutic targeting in acute lung injury.
Highlights
Prolonged exposure to hyperoxia has deleterious effects on the lung, provoking both inflammation and alveolar injury
An integrative analysis of changes across all immune populations of the lung has not yet been undertaken. To address this gap and develop further potential therapeutic targets, we used time-of-flight mass cytometry (CyTOF)[19] to deeply phenotype immune cells in lung parenchyma and bronchoalveolar space of mice breathing room air and mice exposed to 48 hours of hyperoxia
Immune cells were isolated from whole lung parenchyma, and in the independent experiment, from bronchoalveolar lavage fluid (BALF) of C57BL/6 mice breathing room air (FiO2 = 21%) and mice exposed to 48 hours of hyperoxia (FiO2 > 95%)
Summary
Prolonged exposure to hyperoxia has deleterious effects on the lung, provoking both inflammation and alveolar injury. An integrative analysis of changes across all immune populations of the lung has not yet been undertaken To address this gap and develop further potential therapeutic targets, we used time-of-flight mass cytometry (CyTOF)[19] to deeply phenotype immune cells in lung parenchyma and bronchoalveolar space of mice breathing room air and mice exposed to 48 hours of hyperoxia. At this early experimental time point, the exudative www.nature.com/scientificreports injurious phase of hyperoxic lung injury has not yet developed[20,21] and in keeping with this, there was no histologic evidence of alveolar damage. Our findings illustrate the complexity of early immune-modulatory effects of hyperoxia and potentially have therapeutic implications for specific cell targeting in acute lung injury
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