Kuypers Elke, Willems Monique G M, Jellema Reint K, Kemp Matthew W, Newnham John P, Delhaas Tammo, Kallapur Suhas G, Jobe Alan H, Wolfs Tim G A M, Kramer Boris W
Department of Pediatrics, School of Mental Health and Neuroscience, School of Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia.
Pediatr Res. 2015 Jan;77(1-1):29-35. doi: 10.1038/pr.2014.152. Epub 2014 Oct 6.
Intrauterine inflammation activates the fetal immune system and can result in organ injury and postnatal complications in preterm infants. As the spleen is an important site for peripheral immune activation, we asked how the fetal spleen would respond to intrauterine inflammation over time. We hypothesized that intraamniotic lipopolysaccharide (IA LPS) exposure induces acute and persistent changes in the splenic cytokine profile and T-cell composition that may contribute to the sustained fetal inflammatory response after chorioamnionitis.
Fetal sheep were exposed to IA LPS 5, 12, and 24 h and 2, 4, 8, or 15 d before delivery at 125 d of gestational age (term = 150 d). Splenic cytokine mRNA levels and cleaved caspase-3, CD3, and Foxp3 expression were evaluated.
IA LPS increased interleukin (IL)1, IL4, IL5, and IL10 mRNA by twofold 24 h after injection. Interferon gamma increased by fivefold, whereas IL23 decreased 15 d post-LPS exposure. Cleaved caspase-3-positive cells increased 2 and 8 d after LPS exposure. CD3 immunoreactivity increased within 5 h with increased Foxp3-positive cells at 12 h.
Intrauterine inflammation induced a rapid and sustained splenic immune response with persistent changes in the cytokine profile. This altered immune status may drive sustained inflammation and injury in other fetal organs.
宫内炎症会激活胎儿免疫系统，并可能导致早产儿出现器官损伤和产后并发症。由于脾脏是外周免疫激活的重要部位，我们研究了胎儿脾脏随时间推移对宫内炎症会如何反应。我们假设羊膜腔内注射脂多糖（IA LPS）会引起脾脏细胞因子谱和T细胞组成的急性和持续性变化，这可能导致绒毛膜羊膜炎后胎儿持续的炎症反应。
在妊娠125天（足月为150天）分娩前5、12和24小时以及2、4、8或15天，给胎羊注射IA LPS。评估脾脏细胞因子mRNA水平以及裂解的半胱天冬酶-3、CD3和Foxp3的表达。
注射IA LPS后24小时，白细胞介素（IL）1、IL4、IL5和IL10的mRNA增加了两倍。γ干扰素增加了五倍，而LPS暴露后15天IL23减少。LPS暴露后2天和8天，裂解的半胱天冬酶-3阳性细胞增加。CD3免疫反应性在5小时内增加，12小时时Foxp3阳性细胞增加。
宫内炎症诱导了快速且持续的脾脏免疫反应，细胞因子谱持续变化。这种改变的免疫状态可能会导致其他胎儿器官持续的炎症和损伤。
