Abstract

The Receptor for Advanced Glycation End-products (RAGE) is a transmembrane, multi-ligand cell surface receptor highly expressed in pulmonary tissue, where it plays a critical role in mediating inflammatory responses. Under chronic toxicant exposure, often associated with cigarette, e-cigarette, and diesel particulate, RAGE transitions from a protective to a deleterious state, contributing to pathological processes. In adult models, RAGE's role in the development of lung disease has been well studied, yet in the context of lung development RAGE has not been well studied with a small number of clinical papers finding increased levels of RAGE in bronchopulmonary dysplasia(BPD) and respiratory distress syndrome (RDS). Using a lung-specific Tet-On inducible model, we investigated the effects of RAGE upregulation from conception and during a later stage of lung development. Previous studies have established that RAGE overexpression during early embryogenesis induces substantial lung tissue malformations, with severity contingent on the duration of exposure. These malformations are tied to significant increases in apoptosis and decreases in alveolar type 1 and type 2 cells. Our findings demonstrate that developmental RAGE upregulation significantly suppresses transcription factors NKX2.1 and FoxA2, essential for morphogenesis and alveolarization. This loss leads to decreased alveolar type 2 cells and surfactant protein C levels. These losses provide evidence for the pathogenesis of the simplified lung architecture found in H&E stains. Furthermore, the cellular stress induced by RAGE overexpression correlates with pronounced elevations in mitochondrial respiration, ROS levels, and ATP production. Mechanistically, we observed preferential activation of the PI3K signaling cascade via increases in active AKT with a concurrent loss of MAPK signaling via decreases of active ERK and active p38, implicating a shift in apoptotic regulation. Noting this, we measured the effects of RAGE on an array of apoptotic markers. It was found that apoptosis was increased in response to RAGE via upregulation of TRAIL R2-dependent apoptotic pathways, changes in cell cycle progression, alterations of insulin-like growth factor-binding proteins, and modification of pro- and anti-apoptotic factors. Interestingly, the two treatment groups increased apoptosis in unique and shared pathways. In conclusion, this dissertation shows that the damage associated with RAGE upregulation during lung development is in part due to decreases in transcription factors, increased mitochondrial demand, and increased apoptotic signaling. This research has provided the groundwork needed to understand and treat developmental lung diseases. Further research into the inflammatory effects of and specific ties to disease models will provide the needed next steps in this field of research.

Degree

PhD

College and Department

Life Sciences; Physiology and Developmental Biology

Rights

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