Event

Title: New biophysical and immunoregulatory mechanisms in neutrophil extracellular trap mediated lung dysfunction in cystic fibrosis

Committee members:
Dr. Gregg A. Duncan, Chair
Dr. Erika Moore
Dr. Katharina Maisel
Dr. Diego Preciado

Dr. David Mosser, Dean's Representative

 

Abstract: Mucus acts as a defensive barrier in the airways by trapping inhaled particles within the mucin glycoprotein gel network and clearing them from the airway via mucociliary transport performed by the underlying airway epithelium. Cystic fibrosis (CF) is a muco-obstructive disease caused by the buildup of thick mucus with an aberrant composition that is unable to be effectively cleared, resulting in occluded airways. The impairment of mucociliary transport also leads to a state of neutrophilic hyper-inflammation in the airways of CF patients that is not well controlled by current therapeutics. Neutrophil extracellular traps (NETs) are highly upregulated within CF sputum samples and are correlated with worsening lung function in CF. NETs are web-like complexes comprised mainly of decondensed chromatin intermixed with anti-microbial granular proteins that are secreted extracellularly in a process known as NETosis. This dissertation explores i) how NETs affect mucociliary transport and in turn ii) how mucus affects NET release in the context of CF airways. We found that both the chromatin scaffold and granular protein components of NETs differentially affect mucus biophysical properties and transportability across the airway epithelium using bio-inspired biomaterial and human airway tissue culture models. In addition, we show that normal airway mucus inhibits NETosis via mucin proteins using genetically engineered human airway tissue culture models to knockout the expression of certain secreted mucins. We also provide evidence that CF-associated alterations to mucus physicochemical properties, including sialic acid glycosylation and enhanced mucus viscoelasticity lead to upregulated NETosis. In summary, we have advanced understanding of how NETs contribute to mucociliary dysfunction in CF and how mucus modulates NETosis in healthy versus CF airways. Ultimately, this research provides novel models of NETosis in the airways and will help inform the design of new anti-NET therapeutics to improve treatment of CF and other related muco-obstructive lung diseases.