Hyperoxic Exposure of Immature Mice Increases the Inflammatory Response to Subsequent Rhinovirus Infection: Association with Danger Signals.
Hyperoxic Exposure of Immature Mice Increases the Inflammatory Response to Subsequent Rhinovirus Infection: Association with Danger Signals.
复制标题
DOI：
10.4049/jimmunol.1501116
复制
发表时间：
2016-06-01
期刊：
影响因子：
--
通讯作者：
Popova AP
中科院分区：
文献类型：
--
作者：
Cui TX;Maheshwer B;Hong JY;Goldsmith AM;Bentley JK;Popova AP
有早产史和支气管肺发育不良 (BPD) 病史的婴儿在以后的生活中患哮喘和病毒引起的病情加重的风险很高。我们假设，高氧暴露是 BPD 的诱发因素，它会调节先天免疫反应，对病毒感染产生过度的促炎反应。将 2 至 3 日龄的 C57BL/6J 小鼠暴露于空气或 75% 的氧气中 14 天。小鼠在接触 O2 后立即通过鼻内感染鼻病毒 (RV)。感染后 1-12 天评估肺 mRNA 和蛋白质表达、组织学、树突状细胞 (DC) 和气道反应性。收集早产儿的气管抽吸物用于 mRNA 检测。高氧会增加肺部 IL-12 的表达，这种表达在暴露后持续长达 12 天。高氧暴露的 RV 感染小鼠表现出 IL-12 进一步增加，IFN-γ、TNF-α、CCL2、CCL3 和 CCL4 表达增加，以及气道炎症和反应性增加。在感染 RV 且暴露在空气中的小鼠中，反应并不显着。在高氧暴露、RV 感染的小鼠中诱导的 IL-12 表达与产生 IL-12 的 CD103+ 肺 DC 的增加有关。高氧还增加了 Clec9a 的表达，Clec9a 是一种 CD103+ DC 特异性受损细胞识别分子。高氧增加了 ATP 代谢物的水平和腺苷受体 A1 的表达，这是细胞损伤和相关信号传导的进一步证据。在人类早产儿中，气管吸出物Clec9a的表达与早产水平呈正相关。高氧暴露会增加 CD103+、Clec9a+ DC 的激活，导致 RV 感染时炎症和气道高反应性增加。在早产儿中，危险信号诱导的 DC 激活可能会促进促炎性气道反应，从而增加呼吸道疾病的发病率。
Infants with a history of prematurity and bronchopulmonary dysplasia (BPD) have a high risk of asthma and viral-induced exacerbations later in life. We hypothesized that hyperoxic exposure, a predisposing factor to BPD, modulates the innate immune response, producing an exaggerated pro-inflammatory reaction to viral infection. Two-to-3 day-old C57BL/6J mice were exposed to air or 75% oxygen for 14 days. Mice were infected intranasally with rhinovirus (RV) immediately after O2 exposure. Lung mRNA and protein expression, histology, dendritic cells (DCs) and airways responsiveness were assessed 1-12 days after infection. Tracheal aspirates from premature human infants were collected for mRNA detection. Hyperoxia increased lung IL-12 expression which persisted up to 12 days post-exposure. 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 hyperoxia-exposed, 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 pro-inflammatory airway responses, thereby increasing respiratory morbidity.