Bronchopulmonary Dysplasia (BPD), a chronic lung disease that occurs in preterm infants, is characterized by inflammation, edema, and decreased alveolarization. Inflammation is a key contributing factor to the development of BPD and increases in leukocyte infiltration into the lung is the greatest source of inflammatory mediators. Lipoxins (LX) are arachidonic acid derived lipids that have been shown to mediate inflammatory resolution by decreasing neutrophil and macrophage infiltration. Aspirin, an anti-inflammatory drug that acetylates COX-2 and changes COX-2 function from a cyclooxygenases to a lipoxygenase, generates a more biologically stable and potent form of lipoxins, 15-epi lipoxins. Resolution pathways initiated by lipoxins or 15-epi lipoxins include binding to the high affinity lipoxin receptor, ALXR. Upon binding, these ligands decrease transcription of pro-inflammatory cytokines and chemokines. Our overall hypothesis is that administration of lipoxin-enhancing therapies during the course of newborn hyperoxic injury will attenuate the inflammatory responses and improve lung structure and function.
In Specific Aim I, we will test the hypothesis that activation of ALXR by lipoxins or 15-epi-lipoxins In lung epithelial cells, specifically Clara cells, will decrease the transcription of chemokines and cytokines through pathways mediated by NF-kB and SOC-2.
In Specific Aim II, we will test the hypothesis that administration of aspirin will decrease pulmonary inflammatory responses and leukocyte infiltration in newborn mouse pups exposed to hyperoxia. Newborn mouse pups will be treated with aspirin or vehicle and exposed to >95% 02. Markers of inflammation, specifically KC and MIP-2, will be measured in mouse lung tissues. Finally, we will test the hypothesis that administration of aspirin to newborn mouse pups exposed to hyperoxia will improve the lung structural deficits associated with hyperoxic injury using lung morphometric analyses. Our goal is to investigate the effects of enhanced inflammatory resolution during the course of hyperoxic injury in a newborn model. These studies will provide insight into the contribution of inflammation to the progression of hyperoxic injury and development of BPD. Bronchopulmonary Dysplasia (BPD) is a chronic lung disease that affects over 50,000 premature infants a year. Therapies to resolve inflammation and improve the lung development could greatly improve the morbidity and mortality of infants affected by BPD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31HL097619-04
Application #
8311687
Study Section
Special Emphasis Panel (ZRG1-SBIB-V (29))
Program Officer
Colombini-Hatch, Sandra
Project Start
2009-09-01
Project End
2012-12-15
Budget Start
2012-09-01
Budget End
2012-12-15
Support Year
4
Fiscal Year
2012
Total Cost
$7,989
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
Britt Jr, Rodney D; Velten, Markus; Locy, Morgan L et al. (2014) The thioredoxin reductase-1 inhibitor aurothioglucose attenuates lung injury and improves survival in a murine model of acute respiratory distress syndrome. Antioxid Redox Signal 20:2681-91
Velten, Markus; Britt Jr, Rodney D; Heyob, Kathryn M et al. (2014) Maternal dietary docosahexaenoic acid supplementation attenuates fetal growth restriction and enhances pulmonary function in a newborn mouse model of perinatal inflammation. J Nutr 144:258-66
Britt Jr, Rodney D; Locy, Morgan L; Tipple, Trent E et al. (2012) Lipopolysaccharide-induced cyclooxygenase-2 expression in mouse transformed Clara cells. Cell Physiol Biochem 29:213-22