Chorioamnionitis-induced fetal gut injury is mediated by direct gut exposure of inflammatory mediators or by lung inflammation

Wolfs, Tim G. A. M.; Kramer, Boris W.; Thuijls, Geertje; Kemp, Matthew W.; Saito, Masatoshi; Willems, Monique G. M.; Senthamaraikannan, Paranthaman; Newnham, John P.; Jobe, Alan H.; Kallapur, Suhas G.

doi:10.1152/ajpgi.00260.2013

Cited by 50 publications

(54 citation statements)

References 43 publications

(54 reference statements)

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“…The current findings confirm and explain our earlier observations, showing that local exposure of the intestinal epithelium to LPS induces lymphocyte influx and impaired gut integrity. 15 In line with these data, in vitro experiments with intestinal epithelial cells have shown that IL-1 supplementation in the culture system increased the permeability of tight junctions. 32,33 These findings indicate that increased intestinal IL-1α levels directly interact with the intestinal epithelial cells and/or resident immune cells to induce adverse intestinal outcomes as seen in the fetal intestine in the course of chorioamnionitis.…”

Section: Il-1α-driven Fetal Gut Inflammationmentioning

confidence: 63%

“…13,14 The first signs of intestinal inflammation were detected 2 days after IA delivery of LPS, and this inflammatory response resulted from direct LPS exposure to the gut and pulmonary-induced systemic inflammation. 15 Importantly, inhibition of IL-1 signaling with an IL-1 receptor antagonist in our chorioamnionitis model largely prevented fetal organ inflammation and its negative sequelae. 16,17 IL-1 signaling is central to antenatal inflammation in multiple animal models, [18][19][20] and IA IL-1α administration in fetal sheep caused inflammation in the chorioamnion with injury to the respiratory and gastrointestinal tract.…”

mentioning

confidence: 84%

“…15 Fetal sheep were randomized to experimental groups as defined in Table 1. Fetal surgery was performed at 116 or 121 days of gestational age (GA) (term~150 days).…”

Section: Experimental Procedures and Designmentioning

confidence: 99%

“…15 Briefly, fetal lung isolation: a catheter was connected to an osmotic pump to administer IL-1α or saline for controls. The trachea and esophagus were ligated to prevent contact with the amniotic fluid; isolation of the fetal gastrointestinal tract: a catheter was placed via the esophagus into the stomach and an osmotic pump was used to administer IL-1α or saline for controls.…”

Section: Experimental Procedures and Designmentioning

confidence: 99%

“…15 Briefly, ileal cryosections (4 μm) were incubated with anti-ZO-1 followed by Texas Red-conjugated goat-anti-rabbit as a secondary antibody and 4′,6′-diamino-2-phenyl indole as a stain for the nuclei. The distribution of ZO-1 was examined in × 400 magnification using an AxioCam MRc5 camera (Zeiss, Jena, Germany) mounted on an ECLIPSE E800 fluorescence microscope (Nikon, Amsterdam, The Netherlands).…”

Section: Immunofluorescencementioning

confidence: 99%

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

Nikiforou

Kemp

Gorp

et al. 2016

Laboratory Investigation

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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...

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Section: Il-1α-driven Fetal Gut Inflammationmentioning

confidence: 63%

mentioning

confidence: 84%

“…15 Fetal sheep were randomized to experimental groups as defined in Table 1. Fetal surgery was performed at 116 or 121 days of gestational age (GA) (term~150 days).…”

Section: Experimental Procedures and Designmentioning

confidence: 99%

Section: Experimental Procedures and Designmentioning

confidence: 99%

Section: Immunofluorescencementioning

confidence: 99%

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