Date on Master's Thesis/Doctoral Dissertation

5-2013

Document Type

Master's Thesis

Degree Name

M.S.

Department

Pharmacology and Toxicology

Committee Chair

Roman, Jesse

Author's Keywords

Tobacco; Matrix; Nicotine; Collagen; Lung; Tissue remodeling

Subject

Nicotine--Physiological effect; Lungs--Pathophysiology

Abstract

Tobacco-related chronic lung diseases are characterized by alterations in lung architecture, leading to decreased lung function and airflow limitation. Knowledge of the exact mechanisms involved in tobacco-induced tissue remodeling and inflammation remains incomplete. We hypothesized that nicotine, a component of tobacco, stimulates the expression of extracellular matrices leading to relative changes in lung matrix composition, which may affect immune cells entering the lung during inflammation. We found that nicotine stimulated collagen type I mRNA and protein expression in a dose- and time-dependent manner in primary lung fibroblasts. The stimulatory effect of nicotine was inhibited in lung fibroblasts harvested from mice with a7 nicotinic acetylcholine receptor (nAChR) knockout mutations. Testing the potential role of these events on immune cell function, U937 monocytic cells, expressing the interleukin-1ß (IL- 1ß) gene promoter fused to a reporter gene, were cultured atop extracellular matrices derived from nicotine-treated lung fibroblasts. These cells expressed more IL-1ß than those cultured atop matrices derived from untreated fibroblasts, and antibodies against a collagen receptor, a2ß1 integrin receptor, inhibited the effect. Nicotine-stimulated fibroblast proliferation via MEK-1/Erk, unveiling a potentially amplifying pathway. In vivo, nicotine increased the presence of collagen type I in the lung, primarily around the airways. These observations suggest that nicotine stimulates fibroblast proliferation and their expression of collagen type I, thereby altering the relative composition of the lung matrix without impacting the overall lung architecture; this ‘transitional remodeling’ may influence inflammatory responses after injury.

Download

Share

COinS