There are 2 primary focuses of the research in this proposal: 1, to study the secretion and clearance kinetics of the surfactant proteins SP-A, SP-B, and SP-C in the preterm in the presence and in the absence of surfactant treatments, and 2, to investigate the causes and mediators of the pulmonary edema characteristic of the preterm lung that can secondarily interfere with surfactant function. All experiments will be performed in ventilated preterm lambs with or without surfactant treatments, or in term newborn lambs. To evaluate surfactant protein secretion kinetics and the relationships between the proteins and saturated phosphatidylcholine (Sat PC) we will study preterm and term lambs after the airway instillation of 35S-methionine and 3H-palmitic acid. We will then prepare 35S surfactant protein and 3H phospholipid labeled natural sheep surfactant and give trace or treatment doses to the preterm. The airspace clearance and lung tissue localization will be measured versus time to establish the fate of the proteins and the time relationships with Sat PC. Since surfactant used clinically are organic solvent extracts of natural surfactants that lack SP-A, we will test the effects of such a surfactant prepared from natural sheep surfactant on endogenous surfactant metabolism using a model with different lungs of the same animal treated with either natural or organic solvent extracted surfactant. Morphometry will be used to characterize the impact of surfactant treatments on the preterm lung, with the focus being primarily on changes in the type II cell that may reflect surfactant phospholipid recycling in the preterm surfactant treated lung. Other experiments will explore our concept that phospholipid synthetic rates are not the major variable in lung maturation - rather the secretory potential relative to synthetic rate seems to be the critical variable. We will correlate biochemical and morphometric date to make this point. Finally, the protein leaks that occur immediately following delivery and ventilation of the preterm seem to be caused by circulating mediators, based on our preliminary data. We plan to identify these mediators, concentrating initially on platelet activating factor and the arachidonic acid cascade. We will then characterize the maladaptive response of the preterm lung. The result from these experiments will provide information directly relevant for both the design of surfactants for the treatment of respiratory distress syndrome and for interpreting clinical responses in terms of surfactant component mass action. The studies of protein leaks may identify treatment approaches for the tiny preterm.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD012714-15
Application #
3311973
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1979-04-01
Project End
1995-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
15
Fiscal Year
1993
Total Cost
Indirect Cost
City
Torrance
State
CA
Country
United States
Zip Code
90502
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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