PDF(Pubmed)
Abstract：
Organogenesis occurs in the uterus under low oxygen levels (4%). Preterm birth exposes immature newborns to a hyperoxic environment, which can induce a massive production of reactive oxygen species and potentially affect organ development, leading to diseases such as necrotizing enterocolitis. The β3-adrenoreceptor (β3-AR) has an oxygen-dependent regulatory mechanism, and its activation exerts an antioxidant effect. To test the hypothesis that β3-AR could protect postnatal ileal development from the negative impact of high oxygen levels, Sprague-Dawley rat pups were raised under normoxia (21%) or hyperoxia (85%) for the first 2 weeks after birth and treated or not with BRL37344, a selective β3-AR agonist, at 1, 3, or 6 mg/kg. Hyperoxia alters ileal mucosal morphology, leading to increased cell lipid oxidation byproducts, reduced presence of β3-AR-positive resident cells, decreased junctional protein expression, disrupted brush border, mucin over-production, and impaired vascularization. Treatment with 3 mg/kg of BRL37344 prevented these alterations, although not completely, while the lower 1 mg/kg dose was ineffective, and the higher 6 mg/kg dose was toxic. Our findings indicate the potential of β3-AR agonism as a new therapeutic approach to counteract the hyperoxia-induced ileal alterations and, more generally, the disorders of prematurity related to supra-physiologic oxygen exposure.
摘要：
器官发生在低氧水平（4％）下的子宫中。早产使未成熟的新生儿暴露在高氧环境中，可以诱导大量产生活性氧并可能影响器官发育，导致坏死性小肠结肠炎等疾病。β3-肾上腺素受体（β3-AR）具有氧依赖性调节机制，它的活化发挥了抗氧化作用。为了检验β3-AR可以保护出生后回肠发育免受高氧水平的负面影响的假设，Sprague-Dawley幼鼠出生后的前2周在常氧（21％）或高氧（85％）下饲养，并使用或不使用选择性β3-AR激动剂BRL37344治疗，1、3或6mg/kg。高氧改变回肠粘膜形态，导致细胞脂质氧化副产物增加，β3-AR阳性驻留细胞的存在减少，连接蛋白表达降低，破坏了刷子边界，粘蛋白过度生产，血管化受损.用3mg/kg的BRL37344治疗可以防止这些改变，虽然不完全,而较低的1毫克/千克剂量是无效的，较高的6mg/kg剂量是有毒的。我们的发现表明β3-AR激动作为一种新的治疗方法来抵消高氧诱导的回肠改变的潜力，更一般地说,与超生理氧暴露相关的早产儿疾病。
