Infants with a history of prematurity and bronchopulmonary dysplasia have a high risk of asthma and viral-induced exacerbations later in life.We hypothesized that hyperoxic exposure, a predisposing factor to bronchopulmonary dysplasia, modulates the innate immune response, producing an exaggerated proinflammatory reaction to viral infection. Two-to 3-d-old C57BL/6J mice were exposed to air or 75% oxygen for 14 d. Mice were infected intranasally with rhinovirus (RV) immediately after O2 exposure. Lung mRNA and protein expression, histology, dendritic cells (DCs), and airway responsiveness were assessed 1-12 d postinfection. Tracheal aspirates from premature human infants were collected for mRNA detection. Hyperoxia increased lung IL-12 expression, which persisted up to 12 d postexposure. Hyperoxia-exposed RV-infected mice showed further increases in IL-12 and increased expression of IFN-γ, TNF-α, CCL2, CCL3, and CCL4, as well as increased airway inflammation and responsiveness. In RV-infected, air-exposed mice, the response was not significant. Induced IL-12 expression in hyperoxiaexposed, RV-infected mice was associated with increased IL-12-producing CD103+ lung DCs. Hyperoxia also increased expression of Clec9a, a CD103+ DC-specific damaged cell-recognition molecule. Hyperoxia increased levels of ATP metabolites and expression of adenosine receptor A1, further evidence of cell damage and related signaling. In human preterm infants, tracheal aspirate Clec9a expression positively correlated with the level of prematurity. Hyperoxic exposure increases the activation of CD103+, Clec9a+ DCs, leading to increased inflammation and airway hyperresponsiveness upon RV infection. In premature infants, danger signal-induced DC activation may promote proinflammatory airway responses, thereby increasing respiratory morbidity.
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health Grant K23 HL109149.
Copyright © 2016 by The American Association of Immunologists, Inc.
All Science Journal Classification (ASJC) codes
- Immunology and Allergy