Regulatory T Cells And Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension

/Summary Bronchopulmonary dysplasia (BPD) is the most common infantile chronic lung disease that lacks curative therapies. The development of pulmonary hypertension (PH) increases BPD-associated mortality and morbidity. Persistent lung inflammation is central to the pathogenesis of BPD-associated PH (BPD-PH), which is characterized by alveolar and pulmonary vascular simplification and endothelial cell dysfunction. Therefore, this proposal aims to elucidate the mechanisms regulating inflammation in the developing lungs. Regulatory T cells (Tregs) are a subset of CD4+ T cells that regulate innate and adaptive immune responses, prevent tissue damage, and promote the resolution of lung inflammation and injury in adult rodents. Further, Treg density is altered in BPD infants. However, it is unclear if these cells contribute to BPD-PH pathogenesis. Our preliminary data indicate that hyperoxia (HO) exposure decreases Tregs, and Treg depletion potentiates HO-induced experimental BPD-PH in mice. Thus, we propose examining the mechanistic and therapeutic roles of Tregs in BPD-PH using well-established murine models and human biosamples. Our studies also show that Treg depletion decreases endothelial cell (EC) density in neonatal murine lungs. Healthy lung blood vessels are necessary for normal lung development, promoting tissue repair, and mitigating BPD-PH. The interactions between Tregs and lung ECs are unclear. Our compelling data show that Treg depletion increases inflammation and decreases the expression of the pro-angiogenic hormone, adrenomedullin (Adm), and its receptor, receptor activity-modifying protein 2 (Ramp2), in the murine lung ECs. We also show that Adm overexpression decreases HO-induced experimental BPD-PH. Further, we show that human BPD lungs have decreased EC Ramp2 expression and Tregs. Thus, we will test the central hypothesis that Tregs experimental BPD-PH in mice by promoting lung vascular growth, survival, and function via Adm signaling. We will use a unique combination of molecular, cellular, functional, and translational approaches to test this hypothesis. In Aim 1, we will use transgenic neonatal mice, flow cytometry, and single-cell RNA Seq to determine how HO and lipopolysaccharide affect Treg phenotype and function and if adoptive transfer (AT) of Tregs can mitigate experimental BPD-PH. In Aim 2, we will use Adm transgenics and innovative nanoparticles specifically targeting lung ECs to determine if Tregs regulate EC homeostasis and injury in the neonatal lungs via Adm signaling. Finally, in Aim 3, we will perform a prospective cohort study and use a well-curated lung biobank to examine the blood and lung Treg phenotype and density in human infants with and without BPD-PH and correlate them with the disease incidence and severity. We expect our studies to provide new insights into how inflammation and injury are regulated in the developing lungs, and provide a mechanistic rationale for targeting Tregs and Adm pathway to develop novel biomarkers and meaningful therapies for infants with BPD-PH. Project Number: 1R01HL181470-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Binoy Shivanna | Institution: BAYLOR COLLEGE OF MEDICINE, HOUSTON, TX | Award Amount: $773,868 | Activity Code: R01 | Study Section: Pulmonary Vascular Disease and Physiology Study Section [PVP] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL18147001