Lung Mucus Hypersecretion and NQO1
Recruitment status was Recruiting
The research plan proposes translational studies in relevant animal models and human subjects in order to identify host (genetic) susceptibility factors that confer vulnerability to the prototypal air pollutant, ozone. The results will have significant impact upon, and aid in, understanding mechanisms regulating pro-oxidant lung injury, production and secretion of airway mucins, and clearance of respiratory mucus, and adverse health effects, that occur during and following exposure to airborne respiratory irritants.
|Study Design:||Observational Model: Case-Crossover
Time Perspective: Prospective
|Official Title:||Dependency of O3-Induced Lung Mucus Hypersecretion on NQO1|
- Airway Mucociliary Clearance [ Time Frame: 6-24 h post-exposure to filatered air or ozone. ] [ Designated as safety issue: No ]
- Bronchial Epithelial Cells obtained by bronchoalveolar lavage. [ Time Frame: 6-24 h post-exposure to filtered air or ozone. ] [ Designated as safety issue: No ]
Biospecimen Retention: Samples With DNA
Bronchoalveolar lavage specimens.
|Study Start Date:||August 2008|
|Estimated Study Completion Date:||June 2012|
|Primary Completion Date:||October 2011 (Final data collection date for primary outcome measure)|
18-35 yr old healthy subjects with wild type genotype for NQO1.
18-35 yr old healthy subjects who are homozygotic for minor allele of NQO1 Pro187Ser polymorphism
Recent epidemiologic studies have re-ignited an old controversy and opinions are forming as to whether mucus hypersecretion is crucial in the etiology of airway disease. For patients with asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, mucus hypersecretion is now being considered as a risk factor for increased morbidity. The irritant and epithelial membrane effects of O3, a main component of urban smog, upon the airway, and in particular on mucin-type secretory cells and/or interaction with epithelial physiology, have not been investigated vigorously, and at best only superficially, in vivo. We have recently demonstrated in genetically diverse inbred mice that O3-induced pulmonary inflammation and up-regulation of lung mucin secretion and airway mucociliary clearance are host factor dependent. These results match translationally with our evaluations in humans where O3 exposure leads to alterations in mucociliary clearance, and release of a mediator(s) capable of increasing mucin protein synthesis and secretion in vitro. Importantly additional observations by us in a healthy cohort of non-smoking human subjects (n=135) demonstrates that a homozygotic genotype for a single nucleotide polymorphism of the quinone oxido-reductase enzyme, NQO1, protects from the acute irritant effects on air flow that occur with exposure to ambient levels of O3. We have also found that NQO1 can modulate synthesis of mucin proteins by airway epithelial cells in vitro; and in connection with host-factor dependency, that NQO1 is differentially expressed in mice models susceptible and resistant to O3. As a working global hypothesis we propose that exposure to O3 by susceptible humans activates NQO1, generates reactive oxygen metabolites and leads to an increase in MUC5AC mRNA expression and production of mucins by airway epithelial cells. This cycle is re-initiated when O3-induced airway neutrophilia, leads to re-activation of NQO1 by neutrophil elastase, leading to expression and secretion of mucins, disordered mucociliary clearance, and reduced pulmonary function. Investigations are proposed for mice models represented by an O3 susceptible strain, a lung mucin hypersecretion model, and a NQO1 deficient model and simultaneous with translational studies in humans that are segregated genetically between wild-type (NQO1 sufficient) and a single nucleotide polymorphism associated with NQO1 deficiency. The research plan is the initial step towards a definitive link between an ubiquitous urban air pollutant, and genetic factors that regulate oxidant-induced airway hypersecretion of mucus.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00729352
|Contact: W. Michael Foster, PhD||919 668 email@example.com|
|Contact: John Hollingsworth, MD||919 684 firstname.lastname@example.org|
|United States, North Carolina|
|Duke University Medical Center||Recruiting|
|Durham, North Carolina, United States, 27710|
|Contact: W. Michael Foster, PhD 919-668-0382 email@example.com|
|Contact: John Hollingsworth, MD 919 684 4589 firstname.lastname@example.org|
|Principal Investigator: W. Michael Foster, PhD|