In the United States pediatric acute lung injury (ALI) has a mortality rate of 22%, with 11% of children dying from ALI-related pneumonias. Although a high morbidity and mortality is associated with pediatric ALI-related pneumonias, little is known about the processes that cause acute lung injury and the mechanisms that lead to lung recovery. Furthermore, relatively less is known about the age-related changes that occur in the immune system from neonatal to adolescence life and how these age differences affect the lungs'response to ALI. Our preliminary studies suggest differences in macrophage-lymphocyte interactions in neonatal lung in response to an ALI, specifically a lack of MHC class II upregulation in alveolar macrophages in response to TLR4 activation. We believe that this may influence the initial inflammatory response and impair recruitment and proliferation of Tregs into areas of lung injury, thus promoting chronic lung inflammation. Tregs have been shown to be critical orchestrators of lung recovery in an experimental model of adult ALI. In our preliminary studies we found that adoptive transfer of Tregs, but not CD8+ cells or PBS (sham) from adult spleen of C57BL/6 congenic CD45.1 mice attenuated lung neutrophilia and weight loss in neonatal mice with LPS-induced ALI. Our preliminary studies also suggested that Tregs can modulate lung inflammation in the neonate with ALI. The primary goal of this project is to characterize the mechanisms and factors that modulate disease severity from ALI in the neonatal and juvenile lung. We have developed a model of ALI for neonatal mice in which we can deliver an agent into the lungs using a non-invasive intra-tracheal route. Using this model we will study the age related differences that occur in response to an ALI and the mechanisms that allow for recovery. We are also interested in identifying vulnerable periods during lung development in which lung injury can cause lasting changes in the adult lung. In this project we will specifically: (1) characterize age related differences in the early and late inflammatory response to ALI in neonatal (5 day old mice) and juvenile (12 day old mice) (2) study the role of T-regulatory cells in resolving lung inflammation and bacterial clearance in neonatal and juvenile ALI and (3) determine the impact of age on macrophage-lymphocyte interactions during acute lung injury and recovery. We believe that these studies will facilitate detailed examination of neonatal lung responses in a context that is relevant to clinical ALI and will highlight a role for supplemental Tregs as a possible adjuvant therapy in the treatment of neonatal ALI.

Public Health Relevance

Globally, an estimated 1.9 million children less than five years of age die of respiratory tract infections each year. In the United States pediatric acute lung injury (ALI) has a mortality rate of 22%, with 11% of children dying from ALI-related pneumonias. Although a high morbidity and mortality is associated with pediatric ALI-related pneumonias, little is known about the processes that cause acute lung injury and the mechanisms that lead to lung recovery. The goal of our research is to study the mechanisms that underlie the neonatal lung response to acute lung injury and to highlight a role for supplemental T regulatory cells as a possible adjuvant therapy in the treatment of neonatal acute lung injury.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL114800-02
Application #
8680365
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Lin, Sara
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218