The most common pulmonary morbidity of preterm infants is bronchopulmonary dysplasia (BPD). We hypothesize that the initiation of breathing and adaptation of the transitional preterm lung can initiate or propagate a progressive lung injury resulting in BPD. There is almost no information about resuscitation mediated lung injury or guidelines for resuscitation of the preterm despite the ease with which the preterm lung can be injured. We submit a translational research project to perform a factorial assessment of the components of neonatal resuscitation (stretch from high tidal volume and no positive end expiratory pressure, 100% O2, and cold/dry gas) that are likely to injure the preterm lung.
In Specific Aim 1 we will expose the fetal preterm lamb lung to the resuscitation intervention and evaluate the injury caused by that intervention alone and evaluate if subsequent ventilation for 3h causes amplification of the injury.
In Specific Aim 2 we will use antagonists of NFkappaB, IL-1, IL-8 and CD-18 to define the pathways by which stretch injures the preterm lung. Blockade of the injury may allow us to develop therapeutic strategies for decreasing lung injury in the preterm infant. The majority of infants with birth weights <1 kg have been exposed to chorioamnionitis, which causes lung inflammation and alters innate inflammatory responses.
In Specific Aim 3 we will use fetal lambs chronically colonized with Ureaplasma parvum to explore how the chronically inflamed fetal lung responds to resuscitation injury. These studies will provide information for recommendations for resuscitation of the preterm human based on studies that are not possible in the human. Relevance to Public Health: There are no studies or guidelines about how to resuscitate the preterm to avoid lung injury. We will identify the components of resuscitation (stretch, oxygen, cold/dry gas) that may injure the preterm lung, evaluate how the injury develops and how chronic inflammation alters the lung responses. This translational research should result in changes in resuscitation procedures for preterm infants.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD012714-31
Application #
7799839
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Raju, Tonse N
Project Start
1979-04-01
Project End
2011-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
31
Fiscal Year
2010
Total Cost
$248,495
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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
Hillman, Noah H; Moss, Timothy J; Nitsos, Ilias et al. (2012) Moderate tidal volumes and oxygen exposure during initiation of ventilation in preterm fetal sheep. Pediatr Res 72:593-9
Pillow, J Jane; Musk, Gabrielle C; McLean, Carryn M et al. (2011) Variable ventilation improves ventilation and lung compliance in preterm lambs. Intensive Care Med 37:1352-9
Hillman, Noah H; Polglase, Graeme R; Pillow, J Jane et al. (2011) Inflammation and lung maturation from stretch injury in preterm fetal sheep. Am J Physiol Lung Cell Mol Physiol 300:L232-41
Hillman, Noah H; Nitsos, Ilias; Berry, Clare et al. (2011) Positive end-expiratory pressure and surfactant decrease lung injury during initiation of ventilation in fetal sheep. Am J Physiol Lung Cell Mol Physiol 301:L712-20
Hillman, Noah H; Kallapur, Suhas G; Pillow, J Jane et al. (2010) Airway injury from initiating ventilation in preterm sheep. Pediatr Res 67:60-5
Hillman, Noah H; Kallapur, Suhas G; Pillow, J Jane et al. (2010) Inhibitors of inflammation and endogenous surfactant pool size as modulators of lung injury with initiation of ventilation in preterm sheep. Respir Res 11:151
Kunzmann, Steffen; Glogger, Kerstin; Been, Jasper V et al. (2010) Thymic changes after chorioamnionitis induced by intraamniotic lipopolysaccharide in fetal sheep. Am J Obstet Gynecol 202:476.e1-9
Ball, Molly K; Hillman, Noah H; Kallapur, Suhas G et al. (2010) Body temperature effects on lung injury in ventilated preterm lambs. Resuscitation 81:749-54
Kramer, Boris W; Kallapur, Suhas G; Moss, Timothy J M et al. (2010) Modulation of fetal inflammatory response on exposure to lipopolysaccharide by chorioamnion, lung, or gut in sheep. Am J Obstet Gynecol 202:77.e1-9

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