in secondary alveolar septae of neonatal mouse lung.

Children's Mercy Hospitals and Clinics, Kansas City, Missouri, U.S.A.Drug biotransformation can be altered by diet in adults resulting in drug accumulation and toxicity, or in some cases, enhanced elimination. The cytochrome P450 enzymes (CYPs) are a super family of heme-containing phase I enzymes responsible for biotransformation of a significant number of commonly used pharmacologic agents and a large array of endogenous substrates. Previous studies suggest that drug metabolism by CYPs differs between breast-fed and formula-fed infants. The effect of infant diet on the development of functional CYP activity is assessed in this report. Oral doses of caffeine and dextromethorphan were used as pharmacologic probes to track CYP enzyme activity in neonates seen at 6 visits over their first 6 months of life. The caffeine elimination rate constant (k e ) was determined from serum caffeine levels obtained on alternating visits. At all visits, levels of caffeine, dextromethorphan, and their respective metabolites were determined by HPLC in urine samples collected over a 24 hr post-dose period. The serum caffeine k e of infants at their first study visit (2 weeks post-natal age) was unrelated to post-conceptional age. Caffeine elimination was low in infants at this first visit and displayed a significant positive linear correlation with increasing post-natal age (k e ϭ .004 (Age [weeks]) ϩ .001; pϽ0.001). Caffeine k e increased faster in formula-fed infants (slope ϭ .005 95%CI: 0.004, 0.006) than in breast-fed infants (slope ϭ .002 95%CI: 0.001, 0.002) (pϽ0.001) concomitant with increased conversion of caffeine to 3-demethylated metabolites. In contrast, breast feeding significantly increased the urinary fractional molar recovery of 3-methylxanthine (fr3X) [(fr3X) ϭ .004 Age [weeks] ϩ .016; pϽ 0.01] suggesting that this feeding modality produces a relative shunt in metabolism towards 7-demethylated metabolites. Dextromethorphan metabolism, assessed as the fractional molar recovery of 3-hydroxymorphinan (fr3HM), showed a similar marked increase with postnatal age [(fr3HM) ϭ .014 Age [weeks] ϩ .203; pϽ 0.001] that did not differ between diets. The maturation of caffeine elimination does not appear to begin until after birth. Formula feeding appears to accelerate the development of caffeine metabolism but not dextromethorphan. There may be specific ligand(s) unique to infant formula or human breastmilk that modify the developmental regulation of CYP1A gene expression and/or activity. Dietary modification of CYP activity may alter drug bioavailability and increase exposure to modified xenobiotics or endogenous metabolites from a very early age. IDENTIFYING THE MOUSE GENE RESPONSIBLE FOR CONGENITAL PROGRESSIVE HYDRONEPHROSIS (CPH).PD Brophy, J Clarke, RM Raymond Jr. University of Michigan Department of Pediatrics, Ann Arbor, MI.Obstructive uropathy is the leading cause of chronic renal failure and ESRD in children. Understanding the genetic and molecular control of urinary tract development is critical for making an impact o...

Bronchopulmonary dysplasia, a common complication of prematurity, is characterized by inadequate alveolarization. The process of alveolarization, by which the lung forms mature gas-exchanging units, is not well understood. In mice, alveolarizaion occurs during postnatal days four through twelve, when the formation of secondary septa creates thin walled alveoli. The purpose of this study was to investigate the genes involved in this process. RNA was isolated from dissected tips of secondary septa and whole lung tissue of day six postnatal mouse lung. The tips of secondary septa were obtained via laser capture microscopy of frozen sections. Total RNA was isolated from the tip and whole lung samples and amplified in the same manner. Affymetrix gene profiling was then performed, using mouse U74Av2 GeneChips. The signal for galectin-1 mRNA was six fold higher in the secondary septal tips than in whole lung tissue (pϽ0.05). Galectins, or S-type lectins, are beta-galactosidebinding proteins involved in the regulation of cell proliferation, differentiation and apoptosis. Galectin-1 is a homodimer of two 14 kDa subunits. It is the most abundant galectin in the lung. To confirm the relative abundance of galectin-1 in secondary septal tips versus whole lung, immunostaining of sections of day six postnatal and adult mouse lung tissue was performed. Staining for galectin-1 was concentrated in the tips of the secondary septa in the day six postnatal tissue. Furthermore, staining was dramatically increased in the day six mouse lung tissue when compared to staining levels in the adult lung sections. Immunoblot analysis of lung homogenates obtained at different stages of lung development demonstrated that a peak of galectin-1 expression occurs at postnatal days six and twelve, corresponding to the time of alveolarization. The increased expression of galectin-1 at the site and time of ongoing alveolarization suggests that it may play a role in this important aspect of lung development. Supported by NIH grants HL-62861 and HL-07638. SU1498 INHIBITS ALVEOLARIZATION IN NEWBORN MICE.Cho SJ, George CS, Snyder JM, Acarregui MJ. Carver College of Medicine, Univ. of Iowa, Iowa City, IA BACKGROUND: Bronchopulmonary dysplasia (BPD) in premature infants is characterized by inhibited alveolarization and vasculogenesis. Inhibitors of angiogenesis induce emphysema in newborn rats resulting in a phenotype similar to BPD in premature infants. Our goal was to generate a mouse model of inhibited alveolarization that could be employed to explore the mechanisms resulting in, and interventions for BPD. SU1498 is a commercially available compound that inhibits vascular endothelial growth factor receptors. METHODS: Three day old C3H/HeNHsd mice were injected with a single dose of SU1498 (30mg/kg, SC). Lungs of control (sham-injected) and treated mice were inflation fixed on postnatal day 21. Tissue sections were mounted and morphometric analysis was performed to determine the volume density (VD) of air space, tissue, large blood vessels, conducting air...

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