Selective IL-1α exposure to the fetal gut, lung, and chorioamnion/skin causes intestinal inflammatory and developmental changes in fetal sheep.
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.
School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.|Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands.
Maria
M
Nikiforou
School of Women's and Infants' Health, The University of Western Australia, Perth, WA, Australia.
Matthew W
MW
Kemp
Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands.|School of Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
Rick H
RH
van Gorp
School of Women's and Infants' Health, The University of Western Australia, Perth, WA, Australia.|Division of Perinatal Medicine, Tohoku University Hospital, Sendai, Japan.
Masatoshi
M
Saito
School of Women's and Infants' Health, The University of Western Australia, Perth, WA, Australia.
John P
JP
Newnham
School for Nutrition and Translational Research in Metabolism, Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.
Niki L
NL
Reynaert
School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.|Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands.
Leon E W
LE
Janssen
School of Women's and Infants' Health, The University of Western Australia, Perth, WA, Australia.|Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Centre, University of Cincinnati School of Medicine, Cincinnati, OH, USA.
Alan H
AH
Jobe
School of Women's and Infants' Health, The University of Western Australia, Perth, WA, Australia.|Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Centre, University of Cincinnati School of Medicine, Cincinnati, OH, USA.
Suhas G
SG
Kallapur
School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.|Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands.|School of Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
Boris W
BW
Kramer
Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands.|School of Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
Tim G A M
TG
Wolfs
D000818:Animals; D002821:Chorioamnionitis / Q000276:immunology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus / Q000276:immunology*; D053582:Interleukin-1alpha / Q000276:immunology* / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology*; D008168:Lung / Q000276:immunology*; D011247:Pregnancy; D012756:Sheep; D012867:Skin / Q000276:immunology
D016207:Cytokines; D053582:Interleukin-1alpha