Chronic lung disease in prematurity (CLD) may affect as many as 50% of very low birthweight newborns. CLD confers added risk for abnormal neurodevelopmental outcome. Inflammation in response to adequate antioxidant defenses in premature newborns is central to the pathophysiology of lung injury leading to CLD. Present therapy includes glucocorticoids which may adversely affect lung, somatic and central nervous system development.,. Targeted immunotherapy blocking early inflammatory-induced lung injury may prevent the development of CLD and avoid adverse steroid effects. Our hypothesis is that blocking leukocyte influx and/of function will prevent chronic lung disease in the hyperoxia-exposed rodent model. The proposed studies will use hyperoxia-exposed newborn rodents to study the mechanisms of inflammatory effects on lung development in response to serve oxidant stress, as a model of CLD. Neutrophil and macrophage influx/function will be modified by using specific anti- chemokine antibodies and chemokine receptor antagonists. The contribution of key neutrophil functions will e studied in gene knockout mice lacking these functions.
Aim 1 will determine which aspect of neutrophil and/or macrophage influx/function contributes most to biochemical oxidant stress in newborn lung during initiation of hyperoxia-induced lung injury.
Aim 1 will determine which aspect of neutrophil and/or macrophage influx/function contributes most to biochemical oxidant stress in newborn lung during initiation of hyperoxia-induced lung injury.
Aim 2 will determine the specific contributions of leukocyte influx/function to DNA damage, growth arrest, and pathologic apoptosis, which contribute to abnormal alveolar development.
Aim 3 will determine whether blockade of leukocyte function can safely preserve normal alveolar development during recovery from severe oxidant stress.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067021-02
Application #
6622834
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Berberich, Mary Anne
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$308,000
Indirect Cost
Name
Duke University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Chitano, Pasquale; Wang, Lu; Mason, Stanley N et al. (2008) Airway smooth muscle relaxation is impaired in mice lacking the p47phox subunit of NAD(P)H oxidase. Am J Physiol Lung Cell Mol Physiol 294:L139-48
Liao, Lingjie; Ning, Qin; Li, Yuxiang et al. (2006) CXCR2 blockade reduces radical formation in hyperoxia-exposed newborn rat lung. Pediatr Res 60:299-303
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Vozzelli, Michael A; Mason, S Nicholas; Whorton, Mary H et al. (2004) Antimacrophage chemokine treatment prevents neutrophil and macrophage influx in hyperoxia-exposed newborn rat lung. Am J Physiol Lung Cell Mol Physiol 286:L488-93
Auten, Richard L; Ekekezie, Ikechukwu I (2003) Blocking leukocyte influx and function to prevent chronic lung disease of prematurity. Pediatr Pulmonol 35:335-41
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