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.
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.
- 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.