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.
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.
|Gussenhoven, Ruth; Ophelders, Daan R M G; Kemp, Matthew W et al. (2017) The Paradoxical Effects of Chronic Intra-Amniotic Ureaplasma parvum Exposure on Ovine Fetal Brain Development. Dev Neurosci 39:472-486|
|Ophelders, Daan R M G; Gussenhoven, Ruth; Lammens, Martin et al. (2016) Neuroinflammation and structural injury of the fetal ovine brain following intra-amniotic Candida albicans exposure. J Neuroinflammation 13:29|
|Regan, Jodi K; Kannan, Paranthaman S; Kemp, Matthew W et al. (2016) Damage-Associated Molecular Pattern and Fetal Membrane Vascular Injury and Collagen Disorganization in Lipopolysaccharide-Induced Intra-amniotic Inflammation in Fetal Sheep. Reprod Sci 23:69-80|
|Kuypers, Elke; Willems, Monique G M; Jellema, Reint K et al. (2015) Responses of the spleen to intraamniotic lipopolysaccharide exposure in fetal sheep. Pediatr Res 77:29-35|
|Presicce, Pietro; Senthamaraikannan, Paranthaman; Alvarez, Manuel et al. (2015) Neutrophil recruitment and activation in decidua with intra-amniotic IL-1beta in the preterm rhesus macaque. Biol Reprod 92:56|
|Maneenil, Gunlawadee; Kemp, Matthew W; Kannan, Paranthaman Senthamarai et al. (2015) Oral, nasal and pharyngeal exposure to lipopolysaccharide causes a fetal inflammatory response in sheep. PLoS One 10:e0119281|
|Maneenil, Gunlawadee; Payne, Matthew S; Senthamarai Kannan, Paranthaman et al. (2015) Fluconazole treatment of intrauterine Candida albicans infection in fetal sheep. Pediatr Res 77:740-8|
|Viscardi, Rose Marie; Kallapur, Suhas G (2015) Role of Ureaplasma Respiratory Tract Colonization in Bronchopulmonary Dysplasia Pathogenesis: Current Concepts and Update. Clin Perinatol 42:719-38|
|Kallapur, Suhas G; Presicce, Pietro; Rueda, Cesar M et al. (2014) Fetal immune response to chorioamnionitis. Semin Reprod Med 32:56-67|
|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|
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