Lung Mucus Hypersecretion and NQO1

NCT ID: NCT00729352

Last Updated: 2014-09-29

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 60 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2008-08-31
• Study Completion Date: 2012-06-30

Brief Summary

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.

Detailed Description

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.

Conditions

Environmental Exposure; Ozone; Air Pollution; Genetic Susceptibility

Study Design

• Observational Model Type: CASE_CROSSOVER
• Study Time Perspective: PROSPECTIVE

Study Groups

Control group

18-35 yr old healthy subjects with wild type genotype for NQO1.

No interventions assigned to this group

Case group

18-35 yr old healthy subjects who are homozygotic for minor allele of NQO1 Pro187Ser polymorphism

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

-

Exclusion Criteria

-

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Environmental Health Sciences (NIEHS)

NIH

Sponsor Role: lead

Responsible Party

Michael Foster

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Duke University Medical Center

Durham, North Carolina, United States

Countries

United States

Other Identifiers

00008404

Identifier Type: -

Identifier Source: secondary_id

R01ES016347

Identifier Type: NIH

Identifier Source: secondary_id

View Link

16347-CP-001

Identifier Type: -

Identifier Source: org_study_id