Date on Master's Thesis/Doctoral Dissertation

12-2016

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Roman, Jesse

Committee Co-Chair (if applicable)

Arteel, Gavin

Committee Member

Arteel, Gavin

Committee Member

Barve, Shirish

Committee Member

Scott, David

Committee Member

Soucy, Patricia

Author's Keywords

idiopathic pulmonary fibrosis; fibroblast; inflammation; superoxide dismutase; spirometry

Abstract

The median survival for idiopathic pulmonary fibrosis (IPF) patients from diagnosis is a dismal 3 years. This condition is characterized by pulmonary fibroproliferation and excess production and disordered deposition of extracellular matrix (ECM) proteins resulting in obliteration of the original tissue architecture, loss of lung function and eventual death due to respiratory failure. The main hindrance to the development of effective treatments against pulmonary fibrosis is the late detection of its progression and is often of unknown cause. Tobacco smoke represents the most important environmental factor linked to the development of pulmonary fibrosis, with over 60% of IPF patients current or ex-smokers, yet exactly how tobacco influences lung injury and repair is unknown. Research in this area has been hampered by the fact that tobacco is a very complex substance, containing thousands of chemicals. Due to this complexity, I have pursued a different approach and focused on factors, specifically nicotine, which might render the lung susceptible to fibrosis and contribute to the early pathophysiology of IPF. In this dissertation, I extend the work of Dr. Jesse Roman’s lab to investigate additional extracellular matrix modifications via nicotine exposure, including collagen type I. Investigating the cellular receptors and molecular mechanisms mediating the effects of nicotine on fibroblast collagen production/deposition and the potential role of nicotine-induced remodeling in rendering the host susceptible to pulmonary fibrosis are explored through 5 chapters: 1) The effects of nicotine on lung fibroblast proliferation and collagen expression/deposition in vitro and in vivo, and the cholinergic receptors responsible for these effects. 2) The effects of chronic nicotine exposure on injury-induced fibrosis. 3) The impact of chronic nicotine exposure on survival after bleomycin-lung injury. 4) A new diagnostic physiological formula for earlier detection of pulmonary fibrosis progression in IPF patients. 5) A clinical review on Hermansky-Pudlak syndrome, an orphan disease characterized by the natural formation of pulmonary fibrosis. This work provides a detailed understanding of the mechanisms by which tobacco promotes lung remodeling, leading to the development of better tools for diagnostic tracking, care and treatment of these patients.