Author ORCID Identifier
https://orcid.org/0000-0001-9034-4728
Date Available
3-19-2026
Year of Publication
2025
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Medicine
Department/School/Program
Toxicology and Cancer Biology
Faculty
Dr. Xiaoqi Liu
Faculty
Dr. Christine-Fillmore Brainson
Faculty
Dr. Yekaterina Zayetseva
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease, with a median survival of only 2–3 years following diagnosis. In the United States, the disease contributes to more than 40,000 deaths annually, underscoring its severe clinical burden. Alveolar type II (AT2) lung epithelial cells serve as progenitors that maintain alveolar integrity by replenishing epithelial populations and producing surfactants, while fibroblasts and myofibroblasts regulate the extracellular matrix and structural support. In pulmonary fibrosis (PF) injury to AT2 cells promotes cytokine and growth factor release, driving inflammation, fibroblast proliferation, myofibroblast accumulation, and excessive extracellular matrix deposition. Aberrant AT2 cell phenotypes—including senescence, ER stress, telomere dysfunction, and maladaptive transitional states—further contribute to fibrotic remodeling. These changes ultimately stiffen the lung and prevent proper gas exchange to take place and there are no treatment strategies to reverse disease.
PLK1 is a key regulator of mitotic progression, coordinating processes such as centrosome maturation, chromosome segregation, and cytokinesis. PLK1-specific inhibitors, including GSK461364 and Onvansertib, block mitosis and show antitumor activity. I hypothesize that PLK1 facilitates pathogenic processes in pulmonary fibrosis and that inhibition of PLK1 could be a novel treatment strategy. To explore this hypothesis, three complementary set of experiments were performed. In chapter 3, experiments with human lung fibroblasts show that PLK1 inhibition disrupts TGFβ1-induced fibrotic marker expression in human lung cells by RT-qPCR, western immunoblotting and immunofluorescence. Furthermore, both PLK1 inhibitors tested significantly reduced human lung fibroblast cell growth. Results were strongest with the GSK461364 drug compared to the Onvastertib drug. In human PF tissues, PLK1 expression correlates positively with both KRT8⁺ areas and αSMA⁺ fibrotic regions. Additionally, 3D murine lung organoids showed that TGFβ1-induced aSMA⁺ area was attenuated by PLK1 inhibition, but that there was no change in TGFβ1-induced KRT8 expression. In chapter 4, I utilized a bleomycin inhalation mouse model to induce fibrosis. Bleomycin challenged mice treated with the PLK1 inhibitor GSK461364 had less severe lung fibrosis, less PLK1⁺ and αSMA⁺ areas, and less KI67 expression in lungs compared with bleomycin challenged mice treated with placebo. In chapter 5, a novel mouse model of fibrosis driven by an inducible SPC-I73T mutation was used. By spatial transcriptomics, an SPC-mutant induced mouse treated with GSK461364 showed significantly fewer activated AT2s, myofibroblasts, and KRT8+ aberrant AT2 cells than an SPC-mutant mouse treated with placebo or any of the control non-mutant mice. By Gene Set Enrichment Analysis, seven pathological AT2 state signatures, disease-associated hypoxia, inflammation, and EMT pathways were less enriched in the GSK461364 treated SPC mutant mouse compared to the placebo treated SPC mutant mouse. Together, these findings suggest PLK1 inhibition presents a reasonable strategy for further evaluation of therapeutic potential in progressive fibrotic lung diseases.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2025.462
Recommended Citation
Arbogast, Tempany, "INVESTIGATING PLK1 IN PULMONARY FIBROSIS" (2025). Theses and Dissertations--Toxicology and Cancer Biology. 66.
https://uknowledge.uky.edu/toxicology_etds/66
Included in
Circulatory and Respiratory Physiology Commons, Medical Toxicology Commons, Physiological Processes Commons, Toxicology Commons
