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Functional Implications of TNF

The recruitment status of this study is unknown because the information has not been verified recently.
Verified August 2009 by National Institute of Environmental Health Sciences (NIEHS).
Recruitment status was  Recruiting
Sponsor:
Information provided by:
National Institute of Environmental Health Sciences (NIEHS)
ClinicalTrials.gov Identifier:
NCT00729131
First received: August 6, 2008
Last updated: February 22, 2012
Last verified: August 2009
  Purpose

The research plan proposes to develop translational studies in humans that will identify host susceptibility factors that confer vulnerability to the prototypal air pollutant, ozone. Ozone is a ubiquitous urban air pollutant and associated with increased emergency room visits, and co-associates with other air pollutants, to increase mortality in high risk groups (cardio-pulmonary disease) of the population.The results will have significant impact upon and aid in understanding mechanisms of pro-oxidant lung injury, airway hyperresponsiveness, and adverse health effects, that occur during and following exposure to inhalable airborne irritants.


Condition Intervention
Bronchitis
Drug: Etanercept inhibition of ozone-induced airway hyper-responsiveness.

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Prospective
Official Title: Functional Implications of TNF

Resource links provided by NLM:


Further study details as provided by National Institute of Environmental Health Sciences (NIEHS):

Primary Outcome Measures:
  • biologic response to ozone exposure: bronchoalveolar lavage fluid analyzed for inflammatory cytokines, cell differentials, and activated alveolar macrophages. [ Time Frame: Lung lavage evaluated 20 hr post-exposure to ozone. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Alveolar macrophages (collected in lung lavage fluid) will be studied ex vivo for activation state and pro-inflammatory cytokine secretion. [ Time Frame: 20 hr post-exposure to ozone. ] [ Designated as safety issue: No ]

Biospecimen Retention:   Samples With DNA

Bronchoalveolar lavage specimens.


Estimated Enrollment: 100
Study Start Date: August 2008
Estimated Study Completion Date: February 2012
Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
A
Control group: subjects are homozygotic for major allele for TNF-308 promoter polymorphism.
Drug: Etanercept inhibition of ozone-induced airway hyper-responsiveness.
Single dosage of etanercept(50 mg, subcutaneous) given 2 days prior to a laboratory ozone exposure.
Other Names:
  • Only a single group of subjects, known to demonstrate airway hyperresponsiveness at 20 hr post exposure to ozone will be studied in the
  • intervention.
B
Case Group: subjects are homozygotic or heterozygotic for minor allele of TNF-308 promoter polymorphism.

Detailed Description:

Exposure of the airways to air toxins initiates transient and reversible airway injury to both adults and young children. Repetitive exposures of children residing within high oxidant communities leads to impairment of lung growth and pulmonary function, and remodeling of airway epithelial tissues is also suggested to occur. In the completely normal/healthy airway, exposure to ozone (O3), a ubiquitous urban air pollutant, induces an inflammatory response that is characterized by increases in epithelial permeability, neutrophilic infiltration, and bronchial hyperreactivity. Inhalation by humans of the pleiotropic pro-inflammatory cytokine tumor necrosis factor (Tnf) leads to the development of nearly identical responses: hyperresponsiveness of the bronchial airway (AHR), and neutrophil influx. Using controlled exposure to O3 in a laboratory setting, we have recently established a link between a genetic single nucleotide polymorphism (SNP) of TNF gene (-308) and the development of AHR to methacholine within a 24 h time frame, post exposure to O3. In a healthy human study group (n=137) the presence of a common TNF (-308) SNP was found to confer susceptibility to an ambient concentration of O3 (220 ppb, and frequently attained in many cities of the US during the summer months): stratified for ethnicity, Caucasian subjects who were homozygotic (A/A) or heterozygotic (G/A) for the minor allele of the TNF (-308) SNP were 2-times as likely to develop sensitivity to methacholine after O3 as compared to subjects with the wild-type, major allele (G/G) haplotype.

Literature reports suggest that the TNF(-308) polymorphism associates with increased TNF gene transcription and increased Tnf cytokine production. However, the functional significance of this common TNF polymorphism remains uncertain; and moreover, the functional implications of the TNF(-308) polymorphism in the lung remain undeveloped. We hypothesize that subjects either homozygotic (A/A) or heterozygotic (G/A) for the minor allele of the TNF(-308) promoter polymorphism, will demonstrate enhancement in phenotypic responses to O3 including: increased cellular inflammation and secretion of pre-inflammation cytokines, enhanced activation of resident alveolar macrophages, and altered bronchial sensitivity, leading to AHR.

Our research plan is designed to mechanistically investigate the interaction between host factors of humans and exposure to the prototypal air pollutant, ozone. The research plan will expand upon, and enable, a clear assignment of the functional contribution of a common SNP of TNF gene to the initiation of airway hyperresponsiveness, a cardinal feature of inflammatory airway disease.

  Eligibility

Ages Eligible for Study:   18 Years to 35 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population

Healthy non-smokers (18-35 yr) will be recruited from the Duke campus and local community; 50% will be women. Subjects will have a clinical history and lung function screening at protocol entry. Female subjects of childbearing age will have pregnancy testing. We will only recruit subjects with a normal body habitus as an increased BMI may modify sensitivity to O3. Subjects will have lung volumes within predicted normal, and FEV1, and FEF25-75, within range of predicted, and methacholine response less than the mean Mch PC20 dose for non-asthmatic population in our human inhalation laboratory. Atopic status of study subjects will be determined by lack of positive skin test by prick technique (using panel of antigens common to central NC) and without seasonal or perennial allergic symptoms.

Criteria

Inclusion Criteria:

-

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00729131

Contacts
Contact: W. Michael Foster, PhD 919 668 0382 foste028@mc.duke.edu
Contact: John Hollingsworth, MD 919 684 4589 john.hollingsworth@duke.edu

Locations
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: W. Michael Foster, PhD    919-668-0382    foste028@mc.duke.edu   
Contact: John Hollingsworth, MD    919 684 4589    john.hollingsworth@duke.edu   
Principal Investigator: W. Michael Foster, PhD         
Sponsors and Collaborators
  More Information

No publications provided

Responsible Party: W. Michael Foster, Duke University Medical Center
ClinicalTrials.gov Identifier: NCT00729131     History of Changes
Other Study ID Numbers: 00008547
Study First Received: August 6, 2008
Last Updated: February 22, 2012
Health Authority: United States: Federal Government

Keywords provided by National Institute of Environmental Health Sciences (NIEHS):
Ozone, TNF, TNF promoter polymorphism, airway hyperresponsiveness.

Additional relevant MeSH terms:
Bronchitis
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Tract Infections
TNFR-Fc fusion protein
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Inflammatory Agents
Therapeutic Uses
Antirheumatic Agents
Gastrointestinal Agents
Immunologic Factors
Immunosuppressive Agents
Central Nervous System Agents

ClinicalTrials.gov processed this record on August 21, 2014