Intermittent neonatal hypoxia elicits the upregulation of inflammatory-related genes in the adult rat through long-lasting programming effects

Apnea is the most common cause of neonatal hypoxia affecting about 50% of preterm births (30 – 31 weeks), usually due to immature respiratory development. Upregulation of inflammatory genes and pathways in children 7 – 10 years of age has been shown, and there is a known increased risk of insulin resistance in adulthood when the fetus is exposed to maternal hypoxia, but the mechanism is unclear. The long-term metabolic, endocrine, and immunological effects of neonatal intermittent hypoxia (IH) exposure, an accepted model of apnea-induced hypoxia, have not been thoroughly evaluated. Recent studies in rats have shown that perinatal IH exposure can result in oxidative stress, causing a permanent immune response subsequently resulting in features of diabetes mellitus. We have previously examined adult rats exposed to neonatal intermittent hypoxia and perinatal continuous hypoxia, and have found lasting “programming” effects on the HPA axis. We now assess the long term effects of an accepted model of apnea-induced hypoxia using a validated transcriptional bioassay to study the extracellular milieu of adult rats exposed to neonatal intermittent hypoxia. We hypothesize that exposure to neonatal intermittent hypoxia will result in an increased inflammatory state in the adult as a result of long-lasting programming.呼吸暂停（Apnea）是引发新生儿缺氧（neonatal hypoxia）的最常见病因，约累及50%的30~31周早产儿，其发生多因呼吸系统发育未成熟。已有研究证实，7~10岁儿童体内的炎症基因与信号通路存在上调表达；当胎儿暴露于母体缺氧环境时，其成年后罹患胰岛素抵抗的风险显著升高，但具体分子机制尚未阐明。作为公认的呼吸暂停诱导缺氧模型，新生儿间歇性缺氧（neonatal intermittent hypoxia, IH）暴露所带来的长期代谢、内分泌及免疫学效应，目前尚未得到全面评估。近期针对大鼠的研究表明，围产期暴露于IH可引发氧化应激，进而触发永久性免疫应答，最终诱发糖尿病表型。本团队此前针对暴露于新生儿间歇性缺氧及围产期持续性缺氧的成年大鼠开展研究，发现其下丘脑-垂体-肾上腺轴（hypothalamic-pituitary-adrenal axis, HPA axis）存在持久的“程序化”调控效应。本研究现采用经验证的转录组生物测定法（validated transcriptional bioassay），对暴露于新生儿间歇性缺氧的成年大鼠的细胞外微环境展开分析，旨在评估呼吸暂停诱导缺氧的公认模型所带来的长期效应。本研究提出假说：新生儿间歇性缺氧暴露可通过长期程序化调控，导致成年个体体内炎症状态升高。