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Regulation of Airway Smooth Muscle Proliferation: Cytokine-, Glucocorticoid-, and pKa-Dependent Mechanisms

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abstract
Increased mass of airway smooth muscle (ASM) is an important pathogenic mechanism in the obstructive airway disease asthma. Increased volume of ASM has been attributed to both smooth muscle hyperplasia and hypertrophy, and is thought to be driven by increased levels of mitogens and inflammatory mediators in the airway. The effects of polypeptide growth factors and G protein coupled receptor (GPCR) ligands on ASM proliferation have been extensively explored, however regulation of growth by the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α has not been well characterized. Both IL-1β and TNF-α, alone or in combination, have been shown to decrease proliferation of human ASM in vitro stimulated by a variety of growth factors or GPCR agonists and the effect is associated with the ability of the cytokines to induce cyclooxygenase (COX)-2 expression, production of prostaglandin E2 (PGE2), and increase cAMP levels. Because cAMP-dependent protein kinase (PKA) is the primary cAMP effector, it has been assumed to mediate the antimitogenic effects of IL-1β and TNF-α. Even though the role for COX-2 and PGE2 in the anti-mitogenic effects of the cytokines is assumed based on association, no evidence directly implicating PKA exists due to lack of effective and specific inhibitors of PKA in intact cells.
subject
airway smooth muscle
asthma
cytokine
IL-1beta
inflammation
microarray
proliferation
TNF alpha
contributor
Misior, Anna M (author)
Scott D. Cramer, Ph.D. (committee chair)
Reidar Wallin, Ph.D. (committee member)
Suzie V. Torti, Ph.D. (committee member)
John S. Parks, Ph.D. (committee member)
Richard F. Loeser, MD (committee member)
Raymond B. Penn, Ph.D. (committee member)
creator
Misior, Anna M
date
2008-09-28T10:54:08Z (accessioned)
2010-06-18T18:59:36Z (accessioned)
null (available)
2008-09-28T10:54:08Z (available)
2010-06-18T18:59:36Z (available)
2008-06-12 (issued)
degree
null (defenseDate)
Molecular Medicine (discipline)
Wake Forest University (grantor)
PHD (level)
identifier
Figure_E4.tif
Misior_CompleteThesis.pdf
Table_E8.xls
http://hdl.handle.net/10339/14868 (uri)
migration
etd-08262008-094636 (oldETDId)
rights
Release the entire work immediately for access worldwide. (accessRights)
I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Wake Forest University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. (license)
title
Regulation of Airway Smooth Muscle Proliferation: Cytokine-, Glucocorticoid-, and pKa-Dependent Mechanisms

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