Fetal exposures are known to influence lung function in childhood and later life. Although about 7% of all births are categorized as late-preterm (births at 32o-366 wks gestation) and these infants are at increased risk for lung related problems in childhood, this population has been minimally studied for lung outcomes. Fetal exposure to chorioamnionitis (inflammation/infection) can adversely affect lung development and modulate fetal immune function. The most frequent organism associated with fetal inflammation/chronic chorioamnionitis in the human is Ureaplasma spp. We hypothesize that fetal exposure to Ureaplasma spp modulates immune responses and increases the risk of lung disease in early childhood in late-preterm infants. We will test this hypothesis with a clinical study and a parallel experimental study with U. parvum chorioamnionitis in fetal sheep. The clinical study will select cohorts of late preterm infants based on cultures for Ureaplasma spp, and histopathology for chorioamnionitis. Fetal inflammatory responses will be evaluated by cytokine/chemokine profiles in cord blood, molecular phenotypes and immune modulation by cord blood monocytes, and dendritic cells will characterize fetal immune status. The ureaplasma exposed and unexposed late-preterm infants will have lung health assessments at 9 mos and 2 yrs, and pulmonary function tests at 9 mos to evaluate lung outcomes. In parallel experiments we will characterize the inflammatory and immune modulatory responses of fetal sheep to the chorioamnionitis caused by intra-amniotic injection of U. parvum. We will explore the in vivo inflammatory/immune responses to multi-banded antigen (MBA) variability because MBA has been identified in vitro as the virulence factor for U. parvum. We will characterize how gestational age and interval from exposure to delivery modulate the fetal immune and inflammatory responses to U. parvum. We will allow U. parvum exposed fetuses to deliver and measure immune status lung function and structure at 2 wks and 2 mos of age. The experiments are innovative be cause we will focus on late-preterm infants, a large understudied population, to define immune status at birth. We will correlate of fetal ureaplasma exposure and chorioamnionitis with pulmonary outcomes and with immunologic measurements. We will use a clinically relevant model of chorioamnionitis in sheep to evaluate aspects of immune modulation that are not possible in humans. The results will link for the first time a specific and common fetal inflammatory exposure with lung outcomes. The research will be performed by a team of experienced investigators with expertise for each component of the project: the biology of Ureaplasma spp, immune and inflammatory responses in the newborn human and fetal sheep, animal models of chorioamnionitis, and pulmonary assessments of children.

Public Health Relevance

Fetal exposures to chorioamnionitis increase the risks for bronchopulmonary dysplasia and lung abnormalities in childhood in very preterm infants. Late-preterm infants have increased lung disease in childhood, but are a large and minimally studied population. We will evaluate the most common fetal inflammatory exposure - Ureaplasma spp associated chorioamnionitis - in the human and in a relevant sheep model by inflammatory, immune, and lung outcome assessments. The results will provide the information to identify infants at risk and to develop preventative and treatment strategies. Grants/RFA/Relevance

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL097064-04
Application #
8304364
Study Section
Special Emphasis Panel (ZHL1-CSR-H (M2))
Program Officer
Blaisdell, Carol J
Project Start
2009-09-24
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$475,428
Indirect Cost
$127,685
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Rueda, Cesar M; Wells, Casey B; Gisslen, Tate et al. (2015) Effect of chorioamnionitis on regulatory T cells in moderate/late preterm neonates. Hum Immunol 76:65-73
Collins, Jennifer J P; Kallapur, Suhas G; Knox, Christine L et al. (2013) Repeated intrauterine exposures to inflammatory stimuli attenuated transforming growth factor-* signaling in the ovine fetal lung. Neonatology 104:49-55
Snyder, Candice C; Wolfe, Katherine B; Gisslen, Tate et al. (2013) Modulation of lipopolysaccharide-induced chorioamnionitis by Ureaplasma parvum in sheep. Am J Obstet Gynecol 208:399.e1-8
Dando, Samantha J; Nitsos, Ilias; Kallapur, Suhas G et al. (2012) The role of the multiple banded antigen of Ureaplasma parvum in intra-amniotic infection: major virulence factor or decoy? PLoS One 7:e29856
Kallapur, Suhas G; Kramer, Boris W; Knox, Christine L et al. (2011) Chronic fetal exposure to Ureaplasma parvum suppresses innate immune responses in sheep. J Immunol 187:2688-95
Kemp, Matthew W; Saito, Masatoshi; Kallapur, Suhas G et al. (2011) Inflammation of the fetal ovine skin following in utero exposure to Ureaplasma parvum. Reprod Sci 18:1128-37
Berry, Clare A; Nitsos, Ilias; Hillman, Noah H et al. (2011) Interleukin-1 in lipopolysaccharide induced chorioamnionitis in the fetal sheep. Reprod Sci 18:1092-102
Jobe, Alan H (2011) The new bronchopulmonary dysplasia. Curr Opin Pediatr 23:167-72
Collins, Jennifer J P; Kallapur, Suhas G; Knox, Christine L et al. (2010) Inflammation in fetal sheep from intra-amniotic injection of Ureaplasma parvum. Am J Physiol Lung Cell Mol Physiol 299:L852-60
Jobe, Alan H; Kallapur, Suhas G (2010) Long term consequences of oxygen therapy in the neonatal period. Semin Fetal Neonatal Med 15:230-5

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