Ignite Creation Date:
2024-05-05 @ 7:44 PM
Last Modification Date:
2024-10-26 @ 9:53 AM
Study NCT ID:
NCT00729352
Status:
COMPLETED
Last Update Posted:
2014-09-29
First Post:
2008-08-06
Brief Title:
Lung Mucus Hypersecretion and NQO1
Sponsor:
National Institute of Environmental Health Sciences NIEHS
Organization:
National Institute of Environmental Health Sciences NIEHS
Study Overview
Official Title:
Dependency of O3-Induced Lung Mucus Hypersecretion on NQO1
Status:
COMPLETED
Status Verified Date:
2014-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 andor 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 mediators capable of increasing mucin protein synthesis and secretion in vitro Importantly additional observations by us in a healthy cohort of non-smoking human subjects n135 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 00008404 | None | None | None |
| R01ES016347 | NIH | None | httpsreporternihgovquickSearchR01ES016347 |