This proposal describes a 5 year program for academic career development for Noah Hillman who has completed a fellowship in Neontal-Perinatal medicine and is currently a fulltime faculty member of the division of Neonatology/Pulmonary Biology at CCHMC. The research will focus on the mechanisms of lung Injury caused by the resuscitation of preterms using preterm sheep models. This program will provide new evidence for resuscitation guidelines for preterm infants. The transition from a fetus to a newborn requires the initiation of breathing, clearance of fluid from airways, and ventilation of the distal airspaces. Ventilation of the preterm sheep during this transition leads to lung inflammation, cytokine induction, acute phase inflammatory changes, and airway injury. Lung injury from resuscitation may initiate bronchopulmonary dysplasia in extremely premature infants. We have previously used a fetal sheep model to evaluate the effects of resuscitation maneuvers on the lung. In this proposal we will test the hypothesis that ventilation of the surfactant-deficient, preterm lung causes small airway injury and initiates an IL-1 dependant inflammatory response.
The specific aims i nclude l) Regional and temporal differences in ventilator induced lung injury, 2)Role of IL-1 in resuscitation induced lung injury, and 3)Role of PEEP and tidal volume on resuscitation induced lung injury. The research will be conducted under the supervision of Drs. Jobe and Kallapur, who are both experts in lung inflammation and the use of preterm sheep models. The Children's Research Foundation and the Division of Pulmonary Biology provides an ideal setting in which to conduct the proposed research program because of the abundant resources and wide ranging expertise of a talented group of investigators. This proposal incorporates achievable goals that will provide important knowledge on the resuscitation of preterm infants.

Public Health Relevance

Although the majority of preterm infants require some resuscitation at birth, little is known about how best to initiate ventilation while minimizing the risk of lung injury. Ventilation of the preterm infant at birth may contribute to BPD in premature infants. Using fetal sheep models of resuscitation, we can test the maneuvers performed routinely on preterm infants and make recommendations to decrease lung injury.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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Special Emphasis Panel (ZHL1-CSR-O (M1))
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Colombini-Hatch, Sandra
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Saint Louis University
Schools of Medicine
Saint Louis
United States
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Kothe, T Brett; Royse, Emily; Kemp, Matthew W et al. (2018) Epidermal growth factor receptor inhibition with Gefitinib does not alter lung responses to mechanical ventilation in fetal, preterm lambs. PLoS One 13:e0200713
Deptula, Nicole; Royse, Emily; Kemp, Matthew W et al. (2016) Brief mechanical ventilation causes differential epithelial repair along the airways of fetal, preterm lambs. Am J Physiol Lung Cell Mol Physiol 311:L412-20
Hillman, Noah H; Kemp, Matthew W; Miura, Yuichiro et al. (2014) Sustained inflation at birth did not alter lung injury from mechanical ventilation in surfactant-treated fetal lambs. PLoS One 9:e113473
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; Kemp, Matthew W; Noble, Peter B et al. (2013) Sustained inflation at birth did not protect preterm fetal sheep from lung injury. Am J Physiol Lung Cell Mol Physiol 305:L446-53
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
Hillman, Noah H; Kallapur, Suhas G; Jobe, Alan H (2012) Physiology of transition from intrauterine to extrauterine life. Clin Perinatol 39:769-83
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

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