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-1alpha signaling or systemic IL-1alpha-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-1alpha or saline was given into the trachea, stomach, or amniotic cavity 1 or 6 days before preterm delivery. Selective IL-1alpha exposure to the lung, gut, or chorioamnion/skin increased the CD3+ cell numbers in the fetal gut. Direct IL-1alpha 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-alpha mRNA levels in the fetal ileum. With lung or chorioamnion/skin exposure to IL-1alpha, intestinal inflammation was associated with increased numbers of blood leukocytes without induction of intestinal injury or immaturity. We concluded that local IL-1alpha signaling was required for intestinal inflammation, disturbed gut maturation, and mucosal injury in the context of chorioamnionitis.Laboratory Investigation advance online publication, 26 October 2015; doi:10.1038/labinvest.2015.127.
- INTRAAMNIOTIC ENDOTOXIN
- INTRAUTERINE INFECTION
- PRETERM BIRTH
Nikiforou, M., Kemp, M. W., van Gorp, R., Saito, M., Newnham, J. P., Reynaert, N. L., Janssen, L. E., Jobe, A. H., Kallapur, S. G., Kramer, B., & Wolfs, T. (2016). Selective IL-1α exposure to the fetal gut, lung, and chorioamnion/skin causes intestinal inflammatory and developmental changes in fetal sheep. Laboratory Investigation, 96(1), 69-80. https://doi.org/10.1038/labinvest.2015.127