Bronchopulmonary Dysplasia (BPD) in preterm infants is characterized by inflammation underlying ventilator and hyperoxia-induced lung injury that ultimately leads to abnormal lung development. Its incidence remains unchanged despite significant advances in perinatal and neonatal care and it is suggested to result from decreased alveolization due to inflammation. Triggers of inflammation include exposure to a host of pathogens including viruses. In this proposal, the investigators hypothesize that inflammation in immature lungs induces the expression of chemokines that recruit neutrophils and simultaneously alters expression of signaling molecules critical to lung development. Specifically, in a mouse model mimicking viral lung infection, double stranded RNA (dsRNA) activates NF-kB and induces CXC chemokines KC(CXCL1) and MIP-2(CXCL2/3) to recruit neutrophils expressing CXCR2 leading to inflammation. Activation of NF-kB in this model also increases TGF-B1 expression and decreases BMP-4 expression to arrest embryonic lung branching and alveologenesis. This hypothesis will be tested via experiments that will: I) characterize CXC chemokine expression and neutrophil recruitment in a newborn murine model of dsRNA-induced lung inflammation and abnormal lung development;II) determine the specific contribution of CXCR2 in this model by a strategy of antibody- mediated depletion and genetic inhibition of CXCR2;and III)study the mechanism of dsRNA binding and signaling of Toll-like receptor 3 (TLR3) in the activation of human CXC chemokines and lung morphoregulatory genes in cultured human lung epithelial cells. The Principal Investigator on this project will be Vedang A. Londhe, M.D., who will conduct this research under his mentor, Dr. Parviz Minoo, Associate Professor and Director of Basic Research of USC Keck School of Medicine and renowned expert in lung developmental biology. Dr. Londhe's immediate goals are to establish scientific independence, and the support provided by his mentor and this award will ultimately ensure his long-term goal of a career in academic Neonatology.

Public Health Relevance

.The significance of this research to human pathologies is to gain new insights into the pathogenesis of BPD, a common problem affecting a particularly vulnerable population, that may lead to large potential long-term impact on health and health-care costs associated with care of premature babies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL076538-05
Application #
7993569
Study Section
Special Emphasis Panel (ZHL1-CSR-O (O1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2006-12-11
Project End
2011-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
5
Fiscal Year
2011
Total Cost
$121,770
Indirect Cost
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Lopez, Benjamin; Maisonet, Tiffany M; Londhe, Vedang A (2015) Alveolar NF-κB signaling regulates endotoxin-induced lung inflammation. Exp Lung Res 41:103-14
Dayanim, Sara; Lopez, Benjamin; Maisonet, Tiffany M et al. (2014) Caffeine induces alveolar apoptosis in the hyperoxia-exposed developing mouse lung. Pediatr Res 75:395-402
Londhe, Vedang A; Maisonet, Tiffany M; Lopez, Benjamin et al. (2013) Retinoic acid rescues alveolar hypoplasia in the calorie-restricted developing rat lung. Am J Respir Cell Mol Biol 48:179-87
Londhe, Vedang A; Maisonet, Tiffany M; Lopez, Benjamin et al. (2011) Conditional deletion of epithelial IKKβ impairs alveolar formation through apoptosis and decreased VEGF expression during early mouse lung morphogenesis. Respir Res 12:134
Londhe, Vedang A; Sundar, Isaac K; Lopez, Benjamin et al. (2011) Hyperoxia impairs alveolar formation and induces senescence through decreased histone deacetylase activity and up-regulation of p21 in neonatal mouse lung. Pediatr Res 69:371-7
Londhe, Vedang A; Maisonet, Tiffany M; Lopez, Benjamin et al. (2011) A subset of epithelial cells with CCSP promoter activity participates in alveolar development. Am J Respir Cell Mol Biol 44:804-12
Londhe, Vedang A; Nguyen, Hanh T; Jeng, Jade-Ming et al. (2008) NF-kB induces lung maturation during mouse lung morphogenesis. Dev Dyn 237:328-38