Semester

Spring

Date of Graduation

2007

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Joseph K H Ma

Abstract

Diesel exhaust particles (DEP) are the major constituent of ambient particulate matter in urban environments and occupational settings. Exposure to DEP in combination with an allergen has been demonstrated to enhance allergen-related airway inflammation, immunoglobulin (Ig) E production, and airway responsiveness (AR) in human and in animal models. However, the mechanisms behind these effects of DEP are not yet fully understood. In this study, we compared the effects of short-term DEP exposure on ovalbumin (OVA)-mediated airway responses under two exposure protocols using an OVA-allergic rat model. Male Brown Norway rats were sensitized to aerosolized OVA (40.5 +/- 6.3 mg/m3) on days 1, 8, and 15, and challenged with OVA on day 29. The rats were exposed to DEP (20 mg/m3) for 4 h/day for 5 consecutive days either before sensitization (protocol A) or before OVA challenge on days 24-28 (protocol B). Control animals received filtered air and aerosolized saline instead of DEP and OVA, respectively. The results showed that DEP exposure (1) elicited an adjuvant effect on OVA-specific IgE and IgG production in serum under both protocols; (2) significantly reduced OVA-induced airway inflammation and lung injury in protocol A, but increased these markers in protocol B; (3) markedly lowered OVA-induced production of nitric oxide, reactive oxygen species, and interleukin (IL)-10 and IL-12 by alveolar macrophages (AM) in protocol A, but increased these parameters in protocol B; (4) significantly lowered the numbers of T cells and their CD4+ and CD8 + subsets in lung-draining lymph nodes in protocol A, but increased these cell counts in protocol B; (5) reduced intracellular glutathione in AM and lymphocytes in both protocols; and (6) enhanced AR of the OVA-sensitized rats to methacholine challenge in protocol B. These results suggest that the effects of DEP on the immune system, including aggravation or exacerbation of asthma, may be greatly influenced by allergic immune status and time of antigen exposure.

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