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Dissertation/Thesis Abstract

Mechanisms of Lung Remodeling: Role of Mast Cells and Potential Therapeutics
by Savage, Alexandria, Ph.D., Weill Medical College of Cornell University, 2019, 175; 13863642
Abstract (Summary)

Bronchopulmonary dysplasia (BPD) and pulmonary fibrosis (PF) are two diseases which involve extensive lung remodeling. BPD is a frequent sequela of premature birth and oxygen toxicity is a major associated risk factor despite the necessity of oxygen supplementation. Impaired alveolarization, fibrosis, and inflammatory infiltrate that includes mast cells, are hallmarks of BPD. PF is characterized by an inflammatory response that includes macrophages, neutrophils, lymphocytes, and mast cells. Increased mast cell numbers have been observed in both BPD and PF; however, the role of mast cells in their pathogenesis is unknown. We hypothesized that the mast cell hyperplasia seen in these diseases contributes to lung pathology, specifically alveolar simplification, remodeling and fibrosis in BPD, and excessive collagen deposition in lung fibrosis. A murine neonatal hyperoxia model mimicked aspects of BPD wherein neonatal mice were placed in a chamber delivering hyperoxic gas mixture [inspired O2 fraction (FiO2) of 0.8, 0.45, or 0.3] for 2 weeks and then returned to room air for an additional 3 weeks. Lungs from hyperoxia-exposed mice had sustained and increased numbers of mast cells, alveolar simplification and enlargement, and increased lung compliance. The mast cell mediators β-hexosaminidase, histamine, and elastase were also increased in the bronchoalveolar lavage fluid of mice exposed to high oxygen. We also found that the room air recovery period after hyperoxic exposure is important in the development of BPD. Mast-cell-deficiency proved protective by preserving air space integrity and lung compliance. PF, another lung disease with extensive scarring, was also studied in both a murine and in vitro model. Here, we find that mast cells contribute to the development of PF and their mediators can effectively increase collagen synthesis via a distinct pathway other than canonical TGFβ signaling. In both BPD and PF, we inhibited prolyl hydroxylases with Roxadustat. We find that Roxadustat is able to ameliorate fibrotic phenotypes typically seen in these diseases. Collectively, these data show that mast cells play a significant role in phenotypes of lung fibrosis and also that pharmacological inhibition of prolyl hydroxylases may present a therapeutic target for BPD and PF.

Indexing (document details)
Advisor: Silver, Randi B.
Commitee: Levi, Roberto, Rifkind, Arleen, Worgall, Stefan
School: Weill Medical College of Cornell University
Department: Physiology, Biophysics & Systems Biology
School Location: United States -- New York
Source: DAI-B 80/09(E), Dissertation Abstracts International
Subjects: Physiology
Keywords: Lung remodeling, Mast cells, Potential therapeutics
Publication Number: 13863642
ISBN: 978-1-392-14562-3
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