Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USA.
Dis Model Mech. 2019 Oct 21;12(10):dmm040808. doi: 10.1242/dmm.040808.
Fetal exposure to chorioamnionitis can impact the outcomes of the developing fetus both at the time of birth and in the subsequent neonatal period. Infants exposed to chorioamnionitis have a higher incidence of gastrointestinal (GI) pathology, including necrotizing enterocolitis (NEC); however, the mechanism remains undefined. To simulate the fetal exposure to maternal inflammation (FEMI) induced by chorioamnionitis, pregnant mice (C57BL/6J, , or ) were injected intraperitoneally on embryonic day (E)15.5 with lipopolysaccharide (LPS; 100 µg/kg body weight). Pups were delivered at term, and reared to postnatal day (P)0, P7, P14, P28 or P56. Serum and intestinal tissue samples were collected to quantify growth, inflammatory markers, histological intestinal injury, and goblet and Paneth cells. To determine whether FEMI increased subsequent susceptibility to intestinal injury, a secondary dose of LPS (100 µg/kg body weight) was given on P5, prior to tissue harvesting on P7. FEMI had no effect on growth of the offspring or their small intestine. FEMI significantly decreased both goblet and Paneth cell numbers while simultaneously increasing serum levels of IL-1β, IL-10, KC/GRO (CXCL1 and CXCL2), TNF and IL-6. These alterations were IL-6 dependent and, importantly, increased susceptibility to LPS-induced intestinal injury later in life. Our data show that FEMI impairs normal intestinal development by decreasing components of innate immunity and simultaneously increasing markers of inflammation. These changes increase susceptibility to intestinal injury later in life and provide novel mechanistic data to potentially explain why preterm infants exposed to chorioamnionitis prior to birth have a higher incidence of NEC and other GI disorders.
胎儿暴露于绒毛膜羊膜炎会对胎儿的发育产生影响，不仅在出生时，而且在随后的新生儿期也是如此。暴露于绒毛膜羊膜炎的婴儿胃肠道（GI）病理发病率较高，包括坏死性小肠结肠炎（NEC）；然而，其机制尚不清楚。为了模拟绒毛膜羊膜炎引起的胎儿暴露于母体炎症（FEMI），在胚胎第 15.5 天（E）通过腹腔内注射脂多糖（LPS；100μg/kg 体重）对怀孕的小鼠（C57BL/6J，或）进行处理。在足月时分娩幼仔，并饲养至出生后第 0、7、14、28 或 56 天。收集血清和肠组织样本以定量生长、炎症标志物、组织学肠损伤以及杯状细胞和潘氏细胞。为了确定 FEMI 是否增加了随后对肠道损伤的易感性，在 P7 组织采集前，在 P5 时给予第二次 LPS（100μg/kg 体重）剂量。FEMI 对后代的生长或其小肠没有影响。FEMI 显著减少了杯状细胞和潘氏细胞的数量，同时增加了血清中 IL-1β、IL-10、KC/GRO（CXCL1 和 CXCL2）、TNF 和 IL-6 的水平。这些改变依赖于 IL-6，重要的是，增加了以后对 LPS 诱导的肠道损伤的易感性。我们的数据表明，FEMI 通过降低固有免疫成分并同时增加炎症标志物来损害正常的肠道发育。这些变化增加了以后对肠道损伤的易感性，并为潜在解释为什么出生前暴露于绒毛膜羊膜炎的早产儿患 NEC 和其他胃肠道疾病的发病率较高提供了新的机制数据。
