All ETDs from UAB

Advisory Committee Chair

Mark O Bevensee

Advisory Committee Members

Rakesh P Patel

Lawrence S Prince

Erik M Schwiebert

Peter R Smith

Qin Wang

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Zinc is an essential cation for life that is involved in numerous physiology and pathophysiology processes. Despite its wide use as a cytoprotective agent in medications, its cellular and molecular mechanisms of action have not been well established. In order to define the potential therapeutic benefit of zinc, I used several Cystic Fibrosis (CF) and non-CF human airway epithelial cell lines as models in my studies. Extracellular zinc caused release calcium from the endoplasmic reticulum though zinc-sensitive Gq-coupled receptor(s) that may subsequently modulate ion channels. In addition, zinc also exhibited anti-inflammatory effects. Zinc inhibited pro-inflammatory molecular TNFα-induced cytokine and chemokine (e.g., IL-8 and IL-6) secretion by inhibiting one or more upstream mediators of NFκB activation. This inhibitory effect of zinc required an increase in cytosolic zinc. There are several Zinc-Influx Proteins (ZIPs) expressed in CF and non-CF airway epithelia, and their mRNA expression profiles are independent of CF pathogenesis. Together, the combined effects of intracellular and extracellular zinc in modulating ion channels and inflammatory responses may be therapeutic in fighting CF and the associated problems in salt handling and heightened inflammation. Future studies include i) defining the cell surface zinc-selective Gq-coupled receptor(s), ii) defining the specific zinc-sensitive mediator(s) of the NFκB activation, and iii) delineating the mechanisms of intracellular Zinc regulation.

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