Lung Mucus Hypersecretion and NQO1
Condition: Environmental Exposure; Ozone; Air Pollution; Genetic Susceptibility
MeSH terms: Disease Susceptibility; Genetic Predisposition to Disease
Study type: Observational

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.
    

Observational model: Case-Crossover
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Subjects will be healthy adults, non-smokers, recruited from the University campus and
        local community. Fifty% will be female. Recruitment of minority ethnic groups will be
        consistent with census population for central NC. Subjects will have a clinical history and
        lung function screening at protocol entry. Female subjects of childbearing age will have
        pregnancy testing. Equal numbers of NQO1 sufficient and deficient subjects, based upon
        genoytypic pre-screening and stratified by racial background will be studied. Subjects will
        also be genotyped for GSTM1 wild type or null genotype. As individuals with an increased
        BMI may respond strongly to O3 we will only recruit subjects with body habitus within
        normal range for gender, age, and racial group.
      
Biospecimen description: 
      Bronchoalveolar lavage specimens.
    
Keywords: NQO1, ozone, airway mucociliary clearance.