Mechanisms driving persistent airway inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. As secretory immunoglobulin A (SIgA) deficiency in small airways has been reported in COPD patients, we hypothesized that immunobarrier dysfunction resulting from reduced SIgA contributes to chronic airway inflammation and disease progression. In this dissertation we show that polymeric immunoglobulin receptor-deficient (pIgRâ/â) mice, which lack SIgA, spontaneously develop COPD-like pathology as they age. Progressive airway wall remodeling and emphysema in pIgRâ/â mice are associated with an altered lung microbiome, bacterial invasion of the airway epithelium, NF-kappa B activation, leukocyte infiltration, and increased expression of matrix metalloproteinase-12 and neutrophil elastase. Re-derivation of pIgRâ/â mice in germ-free conditions or treatment with the anti-inflammatory phosphodiesterase-4 inhibitor roflumilast prevents COPD-like lung inflammation and remodeling, while repetitive inhalation of bacterial products exacerbates disease. In addition, we demonstrate that p73 is required for PIGR expression in mice, and that mice lacking p73 also develop airway remodeling. These findings show that pIgR/SIgA deficiency in the airways leads to persistent activation of innate immune responses to resident lung microbiota, driving progressive small airway remodeling and emphysema. Based on this data, we propose that altered mucosal immunity due to SIgA deficiency contributes to chronic inflammation and airway remodeling in COPD.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-01192017-144749 |
| Date | 23 January 2017 |
| Creators | Richmond, Bradley Winston |
| Contributors | Emily Hodges, Robert Coffey, Timothy Blackwell, William Tansey, James Goldenring |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-01192017-144749/ |
| Rights | restricted, 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 Vanderbilt 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. |
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