Airway Inflammatory States in Response to Environmental Pollutants and the Influence of Oxidative Balance

Asthma continues to grow as a major health issue worldwide. Epidemiologic evidence points to a link between urban air pollution and exacerbation of asthma cases. The pathophysiology of airway inflammation and hyperresponsiveness in relation to air pollution is not well understood. Based upon previous experiments, this study hypothesized that key components of air pollution, specifically sulfates and aldehydes, enhance allergic sensitization, thus triggering inflammatory processes in airways. Further, it was hypothesized that oxidative stress plays a role in the aforementioned inflammatory enhancement. Sulfite and acrolein were utilized in vitro to test the ability of pollutants generate reactive oxygen species and initiate allergic inflammation in mast cells. Sulfur dioxide was then employed to translate the in vitro findings into a whole animal model. Oxidative pathways were examined in vivo through the use of apocynin, a NAD(P)H oxidase inhibitor and 1[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO) a triterpenoid mimetic of the Nrf2 anti-oxidant DNA binding element. Data obtained confirmed the hypothesis that both acrolein and sulfite induced ROS in mast cells and enhanced degranulation of inflammatory mediators in vitro. Treatment of cells with anti-oxidants ameliorated the effects of the exogenous pollutant stimulation of mast cells. The in vivo model was more complex, however, vi sulfur dioxide exposure did enhance allergic sensitization in a mixed inflammatory state. Type I (IL-6, IL-12, IFN-γ) and type II (IL-13, IL-4, IL-5) inflammatory cytokines were enhanced by exposure of mice to sulfur dioxide. T-cell proliferation was enhanced by exposure to SO2. IgE was actually reduced by SO2 exposure, but IgG1 was heightened. Measures of oxidative stress such as glutathione, NOx, and heme oxygenase-1 confirmed that the oxidative balance was shifted to a pro-oxidative status both in ovalbumin (OVA) sensitized mice and in those exposed to SO2 in combination with OVA. Treatment with anti-oxidants presented a complex picture of systems biology. Apocynin treatment ameliorated the effects of SO2 exposure, however, in animals that were not both allergic sensitized and SO2 exposed, apocynin had an opposite effect on oxidative balance and enhanced inflammatory reactivity. Alternatively, CDDO, operating through the Nrf2 pathway, displayed anti-inflammatory and anti-hyperresponsive properties, shifting the balance of oxidative state towards an enhanced anti-oxidant capacity.

Name thesis:degree_name

Experimental Pathology (Doctoral)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Environmental Toxicology

Grantor

The University of Texas Medical Branch at Galveston

Author dc:creator

• Hochman, Daniel 1971-

Advisors dc:contributor.advisor

• Brooks, Edward
• Ameredes, William

Committee members dc:contributor.committeemember

• Garofalo, Roberto
• Boldogh, Istavan
• Dakhama, Azzeddine

• Asthma
• Inflammation
• Lungs
• RBL-2H3
• Nrf2
• Cytokines
• Acrolein
• Sulfur Dioxide
• air pollution
• oxidative balance
• reactive oxygen species
• CDDO
• plethysmography

Handle dc:identifier.uri

http://hdl.handle.net/2152.3/852

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/852