4d-4 pulmonary airways in adult sheep following intrauterine growth restriction

S68 Oral Submitted Presentations

features akin to adult metabolic syndrome. One way ANOVA defined

differences in hsCRP, uric acid, ALT and GGT in the cluster groups.

Results: The high risk group had higher BMI (x = 27.9, SD = 5.1 vs

x = 20.2, SD = 2.6, p < 0.001), SBP (x = 120.1, SD = 12.0 vs x = 112.1,

SD = 10.4, p < 0.001), insulin (x = 24.6, SD = 15.7 vs x = 10.2, SD = 4.6,

p < 0.001), triglycerides (x = 1.5, SD = 1.0 vs x = 0.9, SD = 0.3,

p < 0.001) and lower HDL (x = 1.2, SD = 0.3 vs x = 1.4, SD = 0.3,

p < 0.001). Markers of inflammation and liver function were higher

in the at risk group; hsCRP (x = 2.15, SD = 4.7 vs x = 0.7, SD = 2.7,

p < 0.001), uric acid (x = 0.34, SD = 0.08 vs x = 0.29, SD = 0.06,

p < 0.001), ALT (x = 21.23, SD = 9.7 vs x16.21, SD = 7.23, p < 0.001)

and GGT (x14.6, SD = 5.9 vs x11.0, SD = 4.0, p < 0.001). The highest

hsCRP levels were only present in children within the cluster who

were also overweight.

Conclusions: This suggests that inflammation exists in at risk

children as early as 13 years, preceding overt atherosclerosis.

It provides clues to the pathogenesis of inflammation in

cardiovascular disease by showing that neither being overweight

or within the metabolic syndrome cluster alone is associated with

raised CRP, but requires the combination of both. It supports

early intervention for preventing childhood obesity and subsequent

cardiovascular disease.

4C-7 Maternal flu infection during pregnancy impacts brain

and behavioral development in the infant monkey

S.J. Short1 *, C.L. Coe1, G. Lubach1, M. Styner2,3, J.H. Glimore.1Department of Psychology, University of Wisconsin, Madison, WI;2Department of Computer Sciences, University of North Carolina,

Chapel Hill, NC; 3Department of Psychiatry, University of North

Carolina, Chapel Hill, NC, USA

E-mail: sjshort@wisc.edu

Aims: Experimental research in rodents and retrospective studies

of children indicate an increased risk for developmental disabilities

and psychopathology following particular viral infections during

pregnancy. Development of a nonhuman primate model that utilizes

a human derived strain of flu is necessary for understanding the

mediating mechanisms and neural impact on the offspring.

Study design: Pregnant rhesus monkeys were infected with the

flu (H3N2 A/Sydney/5/97) 1 month before term. Viral shedding

and generation of flu-specific antibody confirmed the infection.

Offspring are then evaluated: (1) neurobehavior, (2) mother infant

interactions, and (3) brain development.

Subjects: Preliminary assessments of 19 monkeys from control

(n = 7) and virally infected (n = 12) pregnancies.

Outcome Measures: A standardized test battery is used after birth

to assess neonates levels of arousal, motor development, and

attention. Weekly observations of mother and infant interactions

are recorded until 3 months of age. High resolution neuro imaging is

performed at 1 year of age for determining overall gray and white

matter and comparing regions of interest.

Results: Flu infants scored higher on measures of distress and lower

on measures of motor development (p < 0.05) at 2 weeks of age. Flu-

exposed infants initiated autonomy earlier (p < 0.05) despite signs

of distress. MRI analyses revealed significant reductions in total

brain volume and overall hemispheric gray matter (p < 0.05) in flu

animals.

Conclusions: These findings demonstrate that a moderate viral

infection during pregnancy can adversely affect behavioral and

neural development. Reductions in gray matter will be reassessed

after puberty to further examine neurodevelopmental changes in

brain structure and volume.

4D-4 Pulmonary airways in adult sheep following intrauterine

growth restriction

R. Harding1 *, M. O’Reilly1, N. Brew1, K. Snibson2. 1Department of

Anatomy and Cell Biology, Monash University, VIC 3800, Australia,2School of Veterinary Medicine, University of Melbourne, VIC

3010, Australia

E-mail: richard.harding@med.monash.edu.au

Aim: Low birthweight is associated with reduced lung function in

adults but the structural basis is largely unknown. We recently

showed that IUGR leads to fewer, larger alveoli in adult sheep

(Maritz et al., Pediatr Res 2004) but effects on pulmonary airways

have not been examined. Our aim was to determine the effects of

IUGR on airway structure at adulthood.

Methods: Pregnant ewes underwent aseptic surgery for implanta-

tion of fetal aortic and femoral vein catheters. Using microspheres,

umbilical-placental embolization (UPE) was performed daily from

120 days’ gestation until labour onset at term (~147 days). UPE

lowered fetal SaO2 by ~50% and birthweight by 41%. At ~2.2 yrs of

age, offspring were euthanized and organs collected; the right lung

was perfusion fixed via the airway at 20 cmH2O and prepared for

histological examination. Sections (5m) were stained with Masson’s

trichrome and bronchiolar walls analysed morphometrically on

coded slides.

Results: Bronchiolar lumen area, basement membrane perimeter,

total wall thickness, smooth muscle area and collagen area were

not different between IUGR and control sheep. The number of

alveolar attachments, in relation to airway perimeter, was 8% less

in IUGR sheep than in controls (p < 0.05).

Conclusions: Adult sheep that were subjected to IUGR have normal

bronchiolar walls but reduced numbers of alveolar attachments.

Reduced alveolar tethering of small airways, as seen in smokers and

COPD, could contribute to a faster decline in lung function with

age. This could contribute to the association observed in human

populations between low birthweight and reduced lung function.

4D-5 Intrauterine growth restriction alters fetal

lung programming by affecting essential

epithelial-mesenchymal signaling pathways

A. Karadag1 *, R. Sakurai1, J. Belperio3, H. Guang2, M. Desai2,

M.G. Ross2, J.S. Torday1,2, V.K. Rehan1. Departments of 1Pediatrics

and 2Obstetrics and Gynecology, Los Angeles Biomedical Research

Institute at Harbor UCLA, Torrance, California, USA, 2Department

of Pulmonary and Critical Care Medicine, David Geffen School of

Medicine at UCLA, Los Angeles, California, USA

Aims: Intrauterine growth restriction (IUGR) increases the risk of

respiratory compromise throughout postnatal life. However, the

molecular mechanism(s) underlying the respiratory compromise

following IUGR is not known. Since lung development is determined

by spatio-temporally specific alveolar epithelial-mesenchymal

interactions, we hypothesized that IUGR would affect the key

alveolar epithelial-mesenchymal signaling pathways that are

essential for normal lung development.

Study design and Subjects: We utilized a rodent model of 50%

maternal food restriction (MFR) from day 10 of gestation to term

and studied the offspring at postnatal day (PND) 1, 3 weeks, and

9 months.

Outcome measures: Lung morphometry, pulmonary function tests

(PFTs), and Western blotting for the molecular markers of

the key alveolar epithelial-mesenchymal signaling pathways that

determine alveolar structure and function. The specific markers

examined included peroxisome proliferator-activated receptor

gamma (PPARg), vascular endothelial growth factor (VEGF) and

VEGF receptor2 (FLK-1), a-Smooth Muscle Actin (SMA), calponin,

elastin, and glucocorticoid receptor (GCR).

Results: In general, MFR increased the expression of extracellular

matrix proteins aSMA, and calponin, but decreased the expression

of elastin at all time points examined. The expression of VEGF

and its receptor FLK-1, PPARg, and GCR was decreased at 3 wks

and 9 months. Further, in contrast to significant changes in lung