Biomedical Sciences ETDs

Publication Date

7-1-2010

Abstract

One of the components that obstruct the airway in asthma is the sudden and increased secretion of mucus from metaplastic mucous cells in small airways. Because previous studies have shown that the resolution of mucous cell metaplasia (MCM) during prolonged exposure of mice to allergen is mediated by IFN gamma and the Bcl-2 family of proteins, we investigated the regulation and the role of a pro-apoptotic BH3 domain-only protein, Bmf, in airway epithelial cells (AECs) treated with IFN gamma. We hypothesize that Bmf is crucial for IFN gamma-induced cell death. Our findings show that IFN gamma suppressed Bmf expression in a p53-dependent manner. IFN gamma treatment caused nuclear accumulation, increased association of p53 with HDAC1, the reduction of acetylated p53, and the interaction of p53 with the Bmf promoter. This reduction was primarily of the higher molecular weight Bmf that was found to increase cell colony formation in vitro. Bmf was important for the resolution of MCM during prolonged exposure to allergen because the mucous cell numbers did not decline in bmf-/- mice compared to wild-type controls during prolonged exposure to allergen. In addition, bmf-/- mouse airway epithelial cells (MAECs) were resistant to IFN gamma-induced cell death. Previous studies in cancer cell lines have shown that Bmf mediates cell death in response to histone deacetylase inhibitors (HDACis). We found that HDACis increased expression of Bmf in AECs through the displacement of HDAC1 and the acetylation of histones 3 and 4 associated with the Bmf promoter. Bmf-deficient AECs were resistant to HDACi-induced cell death, while expressing Bmf in the bmf-/- MAECs restored this cell death process demonstrating that Bmf is a critical mediator of this cell death process. In conclusion, these findings show that Bmf mediates IFN gamma- and HDACi-induced cell death in AECs and implies that HDACis may be useful for treatment of cancers and for reducing AEC hyperplasia and MCM, thereby reducing mucous hypersecretions and airway obstruction in chronic diseases.

Keywords

airway epithelial cells, Bmf

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Tesfaigzi, Yohannes

First Committee Member (Chair)

Hudson, Laurie

Second Committee Member

Belinsky, Steve

Third Committee Member

Hathaway, Helen

Fourth Committee Member

Wilson, Bridget

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