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Epithelial Reparative Capacity Regulates Extracellular Matrix Dynamics and Innate Immunity

Snyder, Joshua Clair (2009) Epithelial Reparative Capacity Regulates Extracellular Matrix Dynamics and Innate Immunity. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The mammalian lung supports the transport and diffusion of inspired and expired gasses that are critical for aerobic life. With every inspiration the lung is exposed to environmental agents including microbes, virus, and environmental pollutants. In the event that injury occurs the epithelium is repaired by an abundant facultative progenitor pool and a sequestered population of adult tissue stem cells. Chronic lung diseases, such as asthma, chronic obstructive pulmonary disease, and bronchopulmonary dysplasia, are characterized by extensive epithelial remodeling resulting in a reduction to the number of non-ciliated bronchiolar Clara cells. Given the established role for Clara cells as abundant facultative progenitors, these data suggest that epithelial repair has been compromised. In addition to affects on the epithelium, these diseases are also accompanied by extensive subepithelial fibroproliferation, mesenchymal remodeling, and elevated extracellular matrix deposition as well as a profound increase to lung inflammation. It has been postulated, but never tested in vivo that mesenchymal remodeling and uncontrolled deposition of extracellular matrix may be a result of impaired airway epithelial reparative capacity. Moreover, the finding that airway epithelial cells are essential for modulation of innate immunity suggests that the enhanced inflammatory response described in chronic lung disease may be a result of attenuated airway epithelial cell function. Therefore, this dissertation tests the hypothesis that airway epithelial reparative capacity moderates extracellular matrix deposition and innate immunity. Through the use of in vivo models of injury, inflammation, and attenuated Clara cell function, this dissertation research work identifies a previously uncharacterized process in which extracellular matrix is dynamically and reversibly regulated during productive epithelial repair and severely disrupted by blocking stem cell mediated repair. In addition, the use of mouse models of decreased Clara cell abundance and secretion demonstrate airway epithelium modulates pulmonary innate immunity through regulation of macrophage behavior and inhibition of pulmonary inflammation. This work defines two phenotypes that are the result of attenuated epithelial repair and supports the paradigm that epithelial reparative capacity may be a principal determinant of lung disease.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Snyder, Joshua ClairJoshua.Snyder@Duke.Edu
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPitt, Brucebrucep@pitt.eduBRUCEP
Committee MemberBarchowsky, Aaronaab20@pitt.eduAAB20
Committee MemberStripp, BarryBarry.Stripp@Duke.edu
Committee MemberFreeman, Brucefreerad@pitt.eduFREERAD
Committee MemberOury, Timtdoury@pitt.eduTDOURY
Date: 3 June 2009
Date Type: Completion
Defense Date: 30 April 2009
Approval Date: 3 June 2009
Submission Date: 7 May 2009
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Clara cell; Extracellular matrix; Inflammation; Innate Immunity; LPS; Lung Disease; Repair; Stem Cell; Airway epithelium; CCSP
Other ID: http://etd.library.pitt.edu/ETD/available/etd-05072009-163703/, etd-05072009-163703
Date Deposited: 10 Nov 2011 19:44
Last Modified: 15 Nov 2016 13:43
URI: http://d-scholarship.pitt.edu/id/eprint/7823

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