The lungs are a major route for the introduction of environmental pollutants into the body. However, local immune cell populations within the lungs may play a pivotal role in immunocompetence and are likely targets for toxicity from inhaled pollutants. The objective of this study is to determine the effect from ozone (O3) exposure on critical aspects of pulmonary macrophage (PAM) activity involved in induction of the cell-mediated immune (CMI) response. This concerns PAM interactions with cytokines, primarily the interferons (IFNgamma and IFNalpha), and the initiation of events associated with the early and late stages of PAM activation during the course of a CMI reaction against a bacterial pathogen, Listeria monocytogenes. The animal model to be used is the Fisher 344 rat, and in vivo and in vitro exposure regimens will be employed. The existing, although sparse, database suggest that O3 exposure can alter pulmonary antimicrobial defense, in general, and with regards to Listeria, specifically, as well as PAM membrane dynamics and various functional receptor-mediated processes. However, an understanding of the effects of O3 upon cytokine-mediated processes in exposed PAM is lacking. The hypothesis proposed herein is that O3-induced alterations in the ability of PAM to participate in the CMI response are mechanistically linked to changes in the capacity of these cells to form and later interact with immunoregulatory cytokines, primarily the interferons. To be certain that the PAM are the primary cells affected during the course of altered immune function, the effects of O3 upon lung T-lymphocytes, cells critical to PAM priming in the later stages of the CMI response, will also be examined for possible changes in cytokine formation/binding. Using a well-established Listeria host resistance model system to examine CMI function, O3-exposed rats will be analyzed for their resistance to and pulmonary clearance of a sublethal Listeria challenge. The critical role of O3-induced altered PAM-IFN interactions in reduced CMI function will be illustrated by examining air- exposed rats rendered immunincompetent at a defined stage of the antilisterial response. In addition, cytokine release by PAM/T-cells at the early and late stages of resistance will be assessed, as will aspects of cytokine binding. Post-binding IFN metabolism by PAM will also be studied to clarify which IFN processing step might be predominantly affected by O3. In order to measure the ultimate implication from altered PAM cytokine/IFN metabolism, O3-induced changes in IFN/cytokine-inducible structural/functional endpoints will also be examined. All changes in cytokine formation, cytokine/IFN processing by PAM/T- cells, and changes in the inducible functional endpoints will then be examined in the context of the overall changes in Listeria resistance following O3 exposure.
