Functional Implications of TNF
Condition: Bronchitis
MeSH terms: Bronchitis
Study type: Observational

Summary: 
      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.
    

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.
    

Intervention name(s): Etanercept inhibition of ozone-induced airway hyper-responsiveness.
Intervention type(s): Drug
Intervention description(s): Single dosage of etanercept(50 mg, subcutaneous) given 2 days prior to a laboratory ozone exposure.
Other intervention name(s): Only a single group of subjects, known to demonstrate airway hyperresponsiveness at 20 hr post exposure to ozone will be studied in the; intervention.
Intervention MeSH terms: Etanercept
Observational model: Case-Control
Time perspective: Prospective
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.
      
Biospecimen description: 
      Bronchoalveolar lavage specimens.
    
Keywords: Ozone, TNF, TNF promoter polymorphism, airway hyperresponsiveness.