Wolfs Tim G A M, Buurman Wim A, Zoer Bea, Moonen Rob M J, Derikx Joep P M, Thuijls Geertje, Villamor Eduardo, Gantert Markus, Garnier Yves, Zimmermann Luc J I, Kramer Boris W
Department of Surgery, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University Medical Centre, Maastricht, the Netherlands.
PLoS One. 2009 Jun 8;4(6):e5837. doi: 10.1371/journal.pone.0005837.
Chorioamnionitis is the most significant source of prenatal inflammation and preterm delivery. Prematurity and prenatal inflammation are associated with compromised postnatal developmental outcomes, of the intestinal immune defence, gut barrier function and the vascular system. We developed a sheep model to study how the antenatal development of the gut was affected by gestation and/or by endotoxin induced chorioamnionitis.Chorioamnionitis was induced at different gestational ages (GA). Animals were sacrificed at low GA after 2d or 14d exposure to chorioamnionitis. Long term effects of 30d exposure to chorioamnionitis were studied in near term animals after induction of chorioamnionitis. The cellular distribution of tight junction protein ZO-1 was shown to be underdeveloped at low GA whereas endotoxin induced chorioamnionitis prevented the maturation of tight junctions during later gestation. Endotoxin induced chorioamnionitis did not induce an early (2d) inflammatory response in the gut in preterm animals. However, 14d after endotoxin administration preterm animals had increased numbers of T-lymphocytes, myeloperoxidase-positive cells and gammadelta T-cells which lasted till 30d after induction of chorioamnionitis in then near term animals. At early GA, low intestinal TLR-4 and MD-2 mRNA levels were detected which were further down regulated during endotoxin-induced chorioamnionitis. Predisposition to organ injury by ischemia was assessed by the vascular function of third-generation mesenteric arteries. Endotoxin-exposed animals of low GA had increased contractile response to the thromboxane A2 mimetic U46619 and reduced endothelium-dependent relaxation in responses to acetylcholine. The administration of a nitric oxide (NO) donor completely restored endothelial dysfunction suggesting reduced NO bioavailability which was not due to low expression of endothelial nitric oxide synthase.Our results indicate that the distribution of the tight junctional protein ZO-1, the immune defence and vascular function are immature at low GA and are further compromised by endotoxin-induced chorioamnionitis. This study suggests that both prematurity and inflammation in utero disturb fetal gut development, potentially predisposing to postnatal intestinal pathology.
绒毛膜羊膜炎是产前炎症和早产的最重要来源。早产和产前炎症与出生后发育结局受损有关，包括肠道免疫防御、肠道屏障功能和血管系统。我们建立了一个绵羊模型，以研究妊娠和/或内毒素诱导的绒毛膜羊膜炎如何影响肠道的产前发育。在不同的妊娠年龄（GA）诱导绒毛膜羊膜炎。在暴露于绒毛膜羊膜炎2天或14天后，在低GA时处死动物。在诱导绒毛膜羊膜炎后，对近足月动物研究了暴露于绒毛膜羊膜炎30天的长期影响。紧密连接蛋白ZO-1的细胞分布在低GA时显示发育不全，而内毒素诱导的绒毛膜羊膜炎在妊娠后期阻止了紧密连接的成熟。内毒素诱导的绒毛膜羊膜炎在早产动物的肠道中未诱导早期（2天）炎症反应。然而，在内毒素给药14天后，早产动物的T淋巴细胞、髓过氧化物酶阳性细胞和γδT细胞数量增加，这种情况一直持续到近足月动物诱导绒毛膜羊膜炎后30天。在早期GA时，检测到低水平的肠道TLR-4和MD-2 mRNA，在内毒素诱导的绒毛膜羊膜炎期间进一步下调。通过第三代肠系膜动脉的血管功能评估缺血导致器官损伤的易感性。低GA的内毒素暴露动物对血栓素A2模拟物U46619的收缩反应增加，对乙酰胆碱的内皮依赖性舒张反应降低。一氧化氮（NO）供体的给药完全恢复了内皮功能障碍，表明NO生物利用度降低，这不是由于内皮型一氧化氮合酶的低表达。我们的结果表明，紧密连接蛋白ZO-1的分布、免疫防御和血管功能在低GA时不成熟，并因内毒素诱导的绒毛膜羊膜炎而进一步受损。这项研究表明，早产和子宫内炎症都会干扰胎儿肠道发育，可能导致出生后肠道病理状况。
