Selective IL-1α exposure to the fetal gut, lung, and chorioamnion/skin causes intestinal inflammatory and developmental changes in fetal sheep

Abstract

Chorioamnionitis, caused by intra-amniotic exposure to bacteria and their toxic components, is associated with fetal gut inflammation and mucosal injury. In a translational ovine model, we have shown that these adverse intestinal outcomes to chorioamnionitis were the combined result of local gut and pulmonary-driven systemic immune responses. Chorioamnionitis-induced gut inflammation and injury was largely prevented by inhibiting interleukin-1 (IL-1) signaling. Therefore, we investigated whether local (gut-derived) IL-1α signaling or systemic IL-1α-driven immune responses (lung or chorioamnion/skin-derived) were sufficient for intestinal inflammation and mucosal injury in the course of chorioamnionitis. Fetal surgery was performed in sheep to isolate the lung, gastrointestinal tract, and chorioamnion/skin, and IL-1α or saline was given into the trachea, stomach, or amniotic cavity 1 or 6 days before preterm delivery. Selective IL-1α exposure to the lung, gut, or chorioamnion/skin increased the CD3+ cell numbers in the fetal gut. Direct IL-1α exposure to the gut impaired intestinal zonula occludens protein-1 expression, induced villus atrophy, changed the expression pattern of intestinal fatty acid-binding protein along the villus, and increased the CD68, IL-1, and TNF-α mRNA levels in the fetal ileum. With lung or chorioamnion/skin exposure to IL-1α, intestinal inflammation was associated with increased numbers of blood leukocytes without induction of intestinal injury or immaturity. We concluded that local IL-1α signaling was required for intestinal inflammation, disturbed gut maturation, and mucosal injury in the context of chorioamnionitis. Intrauterine infection is the most frequent cause of preterm birth 1 before 28 weeks of gestation. 2 Chorioamnionitis, which is commonly caused by intrauterine bacterial infection, is defined as an inflammation of the fetal membranes, amniotic fluid and placenta. [3][4][5] Bacterial infection of the amniotic cavity results in direct exposure of the lung (by fetal breathing), gastrointestinal tract (by swallowing), skin, and chorioamnion to bacteria and their inflammatory components in the contaminated amniotic fluid. The fetal inflammatory response to chorioamnionitis is associated with multiorgan dysfunction, 6,7 which increase the incidence of periventricular leukomalacia, 8 bronchopulmonary dysplasia, 9 and necrotizing enterocolitis. 10,11 We have used a translational ovine model of chorioamnionitis to investigate the impact of intrauterine inflammation on fetal organs. Using this model, we have shown that intraamniotic (IA) delivery of Escherichia coli lipopolysaccharide (LPS) resulted in an acute inflammatory response in the chorioamnion and increased the influx of inflammatory cells in the respiratory tract within 5 h. 12,13 These immune alterations were rapidly followed by systemic inflammation at the same time point and fetal skin inflammation 12 h after LPS exposure. 13,14 The first signs of intestinal inflammation were detected 2 days after IA delivery of LPS, an...

The Human Ureaplasma Species as Causative Agents of Chorioamnionitis

“…The fetus inspires, swallows, and is bathed in amniotic fluid; therefore, the fetal lungs (68,69), gastrointestinal tract (70,71), and skin (72) are primary sites of inflammation-mediated injury. Exposure to inflammatory mediators may also occur via the placental-fetal circulation, resulting in immunomodulation within the fetal blood (73)(74)(75), lymphoid tissues (76)(77)(78), and distant organs such as the brain (79,80).…”

Dose‐dependent structural and immunological changes in the placenta and fetal brain in response to systemic inflammation during pregnancy

“…Infections account for 20%‐30% of all causes of preterm birth and are a well‐known cause of inflammation‐induced fetal brain injury 13‐23 . The remaining preterm births and fetal brain injuries have no detectable infectious origin, suggesting that inflammation may be involved 24‐27 …”

Global Hypoxia-Ischemia Induced Inflammation and Structural Changes in the Preterm Ovine Gut Which Were Not Ameliorated by Mesenchymal Stem Cell Treatment

“…The number of nuclei and the hypertrophy index in the muscles were calculated as previously described (46). Briefly, the total number of nuclei in muscles was calculated by counting the number of nuclei in muscle layers in a determined area, then multiplying by the surface area (μm immunofluorescence Fetal ileum embedded in optimal cutting temperature solution was cut at a thickness of 4 μm for immunofluorescence staining of GFAP and ZO-1 as previously reported (49). After fixation (15 min in 4% paraformaldehyde), the sections were incubated with 5% normal goat serum in 1% Tween-20 (GFAP) or 10% normal goat serum (ZO-1) for we stained the circular and longitudinal muscle layers for Ki67 as a marker for proliferation.…”