We are seeking continued funding to ask a number of questions about strategies to mature the fetal lung that have the potential to be applied clinically. We hypothesize that single dose, direct fetal administration of hormones alone or in combination will cause rapid and large lung maturational effects in fetuses that have not been previously manipulated. We plan to use hormones (corticosteroids, thyroid hormones, EGF and TGF-alpha) only at doses and treatment durations that are clinically relevant. We will treat preterm sheep by ultrasound guided direct fetal injections and then deliver the preterm lambs 48 hours later. The lambs will be evaluated extensively for postnatal pulmonary adaptation over 4 hours. Physiologic assessments will focus on measurements that translate into improved lung function. We will measure lung volumes, compliances, gas exchange, edema formation, and the responses of the lungs to surfactant treatment. We also will measure biochemical markers of lung maturation - alveolar and lung tissue saturated phosphatidylcholine pool sizes, alveolar surfactant protein A (SP-A), and SP-A, SP-B, and SP-C mRNA levels in lung tissue. The goal is to identify a simple, single dose treatment strategy that can include agents not permeable to the placenta that will effectively and reliably mature the fetal lung.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD020618-08
Application #
3318889
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1985-09-01
Project End
1996-11-30
Budget Start
1992-12-01
Budget End
1993-11-30
Support Year
8
Fiscal Year
1993
Total Cost
Indirect Cost
City
Torrance
State
CA
Country
United States
Zip Code
90502
Pillow, J J; Hall, G L; Willet, K E et al. (2001) Effects of gestation and antenatal steroid on airway and tissue mechanics in newborn lambs. Am J Respir Crit Care Med 163:1158-63
Willet, K E; Jobe, A H; Ikegami, M et al. (2000) Antenatal retinoic acid does not alter alveolization or postnatal lung function in preterm sheep. Eur Respir J 16:101-7
Newnham, J P; Evans, S F; Godfrey, M et al. (1999) Maternal, but not fetal, administration of corticosteroids restricts fetal growth. J Matern Fetal Med 8:81-7
Walther, F J; Jobe, A H; Ikegami, M (1998) Repetitive prenatal glucocorticoid therapy reduces oxidative stress in the lungs of preterm lambs. J Appl Physiol 85:273-8
Jobe, A H; Newnham, J; Willet, K et al. (1998) Fetal versus maternal and gestational age effects of repetitive antenatal glucocorticoids. Pediatrics 102:1116-25
Ikegami, M; Jobe, A H; Havill, A M (1997) Keratinocyte growth factor increases surfactant pool sizes in premature rabbits. Am J Respir Crit Care Med 155:1155-8
Emerson, G A; Bry, K; Hallman, M et al. (1997) Intra-amniotic interleukin-1 alpha treatment alters postnatal adaptation in premature lambs. Biol Neonate 72:370-9
Polk, D H; Ikegami, M; Jobe, A H et al. (1997) Preterm lung function after retreatment with antenatal betamethasone in preterm lambs. Am J Obstet Gynecol 176:308-15
Rebello, C M; Ikegami, M; Ervin, M G et al. (1997) Postnatal lung function and protein permeability after fetal or maternal corticosteroids in preterm lambs. J Appl Physiol 83:213-8
Ikegami, M; Jobe, A H; Newnham, J et al. (1997) Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs. Am J Respir Crit Care Med 156:178-84

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