Lung Mucus Hypersecretion and NQO1

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.

Inclusion Criteria:

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Exclusion Criteria:subjects with current or past smoking history, acute respiratory
illness within six weeks of the study, and significant non-pulmonary disease as determined
by the investigator, pregnancy, age <18 or >35 yr, or inability to understand the
protocol. Subjects will be requested to refrain from anti-histamines, nonsteroidal
anti-inflammatory agents, and supplemental vitamins, e.g. C and E, for 1 week prior to,
and during lab visits for exposures and follow-up measures.

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