Regulatory T cells and Inflammatory Injury of the Developing Murine Lungs

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Abstract/Summary Bronchopulmonary dysplasia (BPD) is the most common chronic infantile lung disease that lacks curative therapies. Further, BPD increases the economic burden and long-term morbidities in preterm infants. Sepsis-mediated persistent lung inflammation is central to the pathogenesis of BPD, which is characterized by interrupted lung development, i.e., alveolar simplification. However, the molecular mechanisms that modulate neonatal lung inflammation are poorly understood. Regulatory T cells (Tregs) are crucial to maintain immune homeostasis and prevent tissue damage. Further, they promote resolution of lung inflammation and injury in adult animals; however, the role of Tregs in BPD pathogenesis remains unclear. Additionally, the mechanisms of Treg recruitment in neonatal lungs are poorly studied. So, we propose to address these knowledge gaps using a neonatal mouse model of lipopolysaccharide (LPS)-induced chronic inflammatory lung injury. Our preliminary studies in neonatal mice indicate that: (1) LPS decreases Tregs and their C-C motif chemokine receptor 5 (CCR5) expression in lungs; and (2) Treg depletion induces inflammation and potentiates LPS- mediated lung injury. Based on our novel data, we will test the central hypothesis that Tregs are necessary and sufficient to protect against LPS-induced inflammatory lung injury in neonatal mice. We will use a unique combination of molecular, cellular, and functional approaches to test this hypothesis. In Aim 1, we will use transgenic mice to determine if Tregs are necessary and sufficient to protect neonatal mice against LPS- induced lung and pulmonary vascular injury and dysfunction. In Aim 2, we will use transgenic mice to examine the mechanisms of lung Treg recruitment. We expect that successful completion of these studies would provide a mechanistic rationale for targeting Tregs to develop meaningful therapies for BPD infants. Our studies also could positively impact other inflammation-related neonatal research areas, including necrotizing enterocolitis, retinopathy of prematurity, and periventricular leukomalacia.