Submitted on November 4, 2008
Revised on December 16, 2008
Accepted on December 29, 2008
AIRWAY INFLAMMATORY CELL RESPONSES TO INTRA-AMNIOTIC LIPOPOLYSACCHARIDE IN A SHEEP MODEL OF CHORIOAMNIONITIS
Fook-Choe Cheah1, J. Jane Pillow2, Boris W. Kramer3, Graeme R Polglase4, Ilias Nitsos5, John P Newnham5, Alan H. Jobe6, and Suhas G. Kallapur1*
1 Cincinnati Children's Hosp. Med Ctr
2 School of Women's and Infant's Health, Univ. of Western Australia
3 Maastricht University Medical Center
4 The University of Western Australia
5 University of Western Australia
6 Children's Hospital Medical Center
* To whom correspondence should be addressed. E-mail: suhas.kallapur{at}chmcc.org.
Chorioamnionitis, a risk factor for bronchopulmonary dysplasia in preterm infants, causes an influx of inflammatory cells into the fetal lung. Using a fetal sheep model, we evaluated the time-course of activation, functional maturity and apoptosis of the leukocytes recruited to the fetal airspaces by lipopolysaccharide (LPS). Time-mated sheep were given intra-amniotic injections with 10 mg E. coli LPS or saline, 2d or 7d prior to preterm delivery at 124d gestation (term is 150d). Both neutrophils and monocytes in broncho-alveolar lavage fluid (BALF) had activated NF-
B after 2d and 7d LPS exposures. These neutrophils and monocytes expressed the activation factor CD11b and the maturation factor PU.1 at 2d, and increased PU.1 expression was detected in macrophages at 7d. Leukocyte oxidative burst activity was greatest at 7d. BALF lipid peroxidation increased 5 fold at 2d, while protein carbonyls increased 8-fold at 7d. Nitrative stress was not detected in the BALF, but leukocytes in the lung expressed NOSII (iNOS). BALF leukocytes expressed the antioxidant peroxiredoxin V. Lung glutathione peroxidase was also increased with LPS exposure. There was minimal apoptosis of airway and lung leukocytes assessed by caspase-3 activation. Intra-amniotic LPS recruits leukocytes to the fetal airspace that have a persistent activation. These results have implications for the pathogenesis of lung inflammatory disorders in the preterm.
