Chorioamnionitis or inflammation in the fetal membranes is present in about 70% of the preterm infants born before 30 weeks gestation and is a major contributor to the morbidity and mortality in this population. Fetal inflammatory response syndrome (FIRS) is present in about 50% of preterm infants exposed to chorioamnionitis and thought to be the mediator of chorioamnionitis induced fetal injury responses. Despite many epidemiological studies implicating FIRS as a strong risk factor for adverse neurological, gastrointestinal and pulmonary outcomes in preterm neonates, very little is known about the mechanism or the pathogenesis of FIRS. A major stumbling block in the progress of understanding how FIRS is initiated or signaled is the lack of appropriate animal models. This proposal will test the hypothesis that fetal exposure to chorioamniontis induces a systemic inflammatory response that is initiated by IL-1 signaling in the amniotic compartment and is modulated by systemic innate immune responses. The experiments will utilize the preterm fetal sheep model of chorioamniontis induced by intraamniotic endotoxin developed by our group that closely mimics human pathology. This application is based on our preliminary data that IL-1 signaling is required to mediate intraamniotic endotoxin induced lung inflammatory responses and that the sheep fetus adapts to repeated exposures to intraamniotic endotoxin with decreased monocyte responsiveness to endotoxin.
In Specific Aim 1 we will define the relative contributions of the chorioamnion, lung and gastrointestinal tract to development of FIRS induced by endotoxin. We will utilize fetal surgical methods developed by our group to isolate each of the organs.
In Specific Aim 2 we will test if intraamniotic IL-1 causes FIRS and determine the requirement of IL-1 signaling in LPS induced FIRS using an IL-1 receptor antagonist.
In Specific Aim 3 we will evaluate fetal adaptation and endotoxin tolerance to repeated exposures of intraamniotic endotoxin. Our long term goals are to understand the mechanisms of systemic inflammation and organ injury responses following exposure to chorioamnionitis. This grant will provide a framework to understand the problem of FIRS at a whole animal level. This work will provide insights necessary to the development of therapeutic strategies such as selective intraamniotic anti-inflammatory therapy to improve outcomes in preterm infants exposed to chorioamnionitis.

Public Health Relevance

Chorioamnionitis and the associated systemic inflammatory responses cause significant morbidity in preterm neonates and are a major public health problem in this population. This grant will define the mechanisms of systemic inflammatory response in a sheep model of chorioamnionitis induced by intraamniotic endotoxin. This knowledge will be essential to developing treatment approaches aimed at improving preterm infant outcomes.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Raju, Tonse N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cincinnati Children's Hospital Medical Center
United States
Zip Code
Hillman, Noah H; Gisslen, Tate; Polglase, Graeme R et al. (2014) Ventilation-induced increases in EGFR ligand mRNA are not altered by intra-amniotic LPS or ureaplasma in preterm lambs. PLoS One 9:e96087
Payne, Matthew S; Kemp, Matthew W; Kallapur, Suhas G et al. (2014) Intrauterine Candida albicans infection elicits severe inflammation in fetal sheep. Pediatr Res 75:716-22
Gisslen, Tate; Hillman, Noah H; Musk, Gabrielle C et al. (2014) Repeated exposure to intra-amniotic LPS partially protects against adverse effects of intravenous LPS in preterm lambs. Innate Immun 20:214-24
Wolfs, Tim G A M; Kramer, Boris W; Thuijls, Geertje et al. (2014) Chorioamnionitis-induced fetal gut injury is mediated by direct gut exposure of inflammatory mediators or by lung inflammation. Am J Physiol Gastrointest Liver Physiol 306:G382-93
Schmidt, Augusto F; Kannan, Paranthaman S; Kemp, Matthew W et al. (2014) Intra-amniotic LPS modulates expression of antimicrobial peptides in the fetal sheep lung. Pediatr Res 76:441-7
Kallapur, Suhas G; Presicce, Pietro; Rueda, Cesar M et al. (2014) Fetal immune response to chorioamnionitis. Semin Reprod Med 32:56-67
Kuypers, Elke; Willems, Monique G M; Collins, Jennifer J P et al. (2014) Altered canonical Wingless-Int signaling in the ovine fetal lung after exposure to intra-amniotic lipopolysaccharide and antenatal betamethasone. Pediatr Res 75:281-7
Lambermont, Verena A; Kuypers, Elke; Collins, Jennifer J P et al. (2014) Effects of intra-amniotic lipopolysaccharide exposure on the fetal lamb lung as gestation advances. Pediatr Res 75:500-6
Kemp, Matthew W; Kannan, Paranthaman Senthamarai; Saito, Masatoshi et al. (2013) Selective exposure of the fetal lung and skin/amnion (but not gastro-intestinal tract) to LPS elicits acute systemic inflammation in fetal sheep. PLoS One 8:e63355
Wolfe, Katherine B; Snyder, Candice C; Gisslen, Tate et al. (2013) Modulation of lipopolysaccharide-induced chorioamnionitis in fetal sheep by maternal betamethasone. Reprod Sci 20:1447-54

Showing the most recent 10 out of 34 publications