Advisory Committee Chair
Christian Faul
Document Type
Dissertation
Date of Award
2024
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Chronic inflammation plays a role in the development and progression of airway diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). COPD is caused primarily by chronic cigarette smoke exposure. Conversely, CF is a single gene disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Although the causes of COPD and CF are different, there are common pathological features. Studies show that chronic inflammation plays a significant role in the pathogenesis of both COPD and CF. Moreover, chronic inflammation induces ageing-associated pathomechanisms like cellular senescence, which exacerbates chronic inflammation. Previous work demonstrates that both chronic inflammation and cellular senescence contribute to COPD development. Furthermore, chronic inflammation is also a hallmark of CF. However, the molecular mechanisms by which chronic inflammation contributes to the complex pathology of COPD and CF have not been fully elucidated. Furthermore, while cellular senescence has been implicated in the pathomechanism of COPD, the role of cellular senescence in CF has not been characterized. The present work demonstrates that fibroblast growth factor receptor (FGFR)-mediated signaling contributes to chronic inflammation in both COPD and CF. Studies on FGFR4 knock out mice demonstrated that FGFR4 plays an essential role in lung inflammation. Furthermore, FGFRs contribute to chronic inflammation in CF as well. Additionally, we show that cellular senescence, a major contributor to chronic inflammation, is activated in CF lungs and the activation of cellular senescence is regulated by FGFRs. To confirm the role of FGFRs in the induction of cellular senescence we demonstrated that FGFR inhibition in CF airways significantly decreased inflammation, cellular senescence and improved mucociliary clearance. Given that chronic inflammation and cellular senescence in COPD and CF are activated through FGFR-mediated signaling, FGFR inhibition could be a potential therapeutic intervention for these disorders. Taken together, this work demonstrates the role of FGFRs in regulating inflammation and cellular senescence in airway inflammatory diseases (COPD and CF). This work also highlights the potential of FGFR inhibitors as therapeutic agents for chronic inflammation and cellular senescence. Overall, this work provides impetus for future investigations of FGFRs as regulators of inflammation and cellular senescence in airway inflammatory diseases and potentially other chronic inflammatory diseases.
Recommended Citation
Easter, Molly, "The Role Of Fibroblast Growth Factor Receptors In Inflammatory Airway Diseases" (2024). All ETDs from UAB. 3846.
https://digitalcommons.library.uab.edu/etd-collection/3846