Degree

Doctor of Philosophy (PhD)

Department

Veterinary Medicine - Interdepartmental Program

Document Type

Dissertation

Abstract

The primary purpose of pulmonary ventilation is to supply oxygen for sustained aerobic respiration. However, a plethora of abiotic insults and airborne pathogens present in the environment are occasionally introduced into the airspaces during inhalation. Multiple layers of host defense, termed the mucociliary escalator, act in concert to eliminate unwanted constituents from the airspaces. Defects in the mucociliary escalator, as exhibited in cystic fibrosis (CF), compromise the mucociliary clearance (MCC) of inhaled pathogens, which favors microbial lung infection and progressive decreases in lung function. In CF, a mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene results in dehydration of the airway surface liquid (ASL) layer. The Scnn1btransgenic (Scnn1b-Tg+) mouse model overexpressing a transgene encoding Sodium channel non-voltage-gated 1, beta subunit(Scnn1b) provides a unique model that recapitulates many pulmonary pathological manifestations of CF, e.g., early onset of disease, ASL layer dehydration, airway inflammation/mucus obstruction, and spontaneous pulmonary bacterial infections. Secondhand smoke (SHS) has been linked to the initiation and progression of ongoing lung diseases. There remains a dearth of knowledge on the immunological consequences chronic SHS exposure inflicts upon muco-obstructive lung diseases such as CF. The Scnn1b-Tg+ mice were exposed to SHS from postnatal (PND)3-21 and lungs phenotypes were compared on PND 22. Compared to filtered-air exposed counterparts, SHS-exposed Scnn1b-Tg+ mice exhibited a significant decrease in Th2-associated responses, i.e., mucous cell metaplasia (MCM) and airway mucus obstruction. SHS was found to suppress Th2-responses by a suppression of Interleukin (IL) 33, a potent Th2stimulator. To test our hypothesis that ablation of IL33 would attenuate MCM and airway mucus obstruction, IL33-deficient Scnn1b-Tg+ mice were generated and lung phenotypes observed at PND 7 and PND 21 exhibited a reduction in MCM but not mucus obstruction. Our studies revealed a possible protective role of IL33 against the development of alveolar space enlargement. Taken together, our studies reveal the importance of IL33 in the pathogenesis of muco-obstructive lung disease.

Date

2-18-2019

Committee Chair

Saini, Yogesh

Available for download on Wednesday, February 16, 2022

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