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Title page for ETD etd-01192017-144749


Type of Document Dissertation
Author Richmond, Bradley Winston
Author's Email Address bradley.richmond@vanderbilt.edu
URN etd-01192017-144749
Title Airway Bacteria Drive a Progressive COPD-Like Phenotype in Mice with Polymeric Immunoglobulin Receptor Deficiency
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Robert Coffey Committee Chair
Emily Hodges Committee Member
James Goldenring Committee Member
Timothy Blackwell Committee Member
William Tansey Committee Member
Keywords
  • polymeric immunoglobulin receptor
  • secretory immunoglobulin A
  • chronic obstructive pulmonary disease
  • mucosal immunity
Date of Defense 2017-01-10
Availability restricted
Abstract
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 (pIgR−/−) mice, which lack SIgA, spontaneously develop COPD-like pathology as they age. Progressive airway wall remodeling and emphysema in pIgR−/− 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 pIgR−/− 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.
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