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.
|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|
|Keywords:||Lung remodeling, Mast cells, Potential therapeutics|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be