Asthma is a chronic lung disorder that continues to increase in prevalence, cost and mortality despite improved treatments. Although the association of allergens with asthma has been extensively investigated, the cellular and molecular mechanisms involved in the development of asthma remain to be fully elucidated. Furthermore, even though there is good epidemiological evidence indicating that both particulate matter (PM) and ozone can exacerbate existing asthma, even less is known regarding the potential mechanisms that are involved. Preliminary data are presented indicating that PM by itself can generate a Th2-like response and airway hyperresponsivenes, which is enhanced by ozone exposure. Additional data support the notion that the effects of PM may be mediated through alveolar macrophages (AM) by apoptotic elimination of immune suppressor AM allowing immune active AM to stimulate T helper cells and cause airway hyperresponsiveness. Consequently, in this proposal the hypotheses will be tested that exposures to PM plus/minus ozone can produce asthma-like symptoms and exacerbate asthma-like inflammation in a well-established murine model (allergen sensitization) by altering AM populations and functional activity. Furthermore, these airborne contaminants target AM to disrupt the normal Th1: Th2 cytokine balance in the lung leading to the airway hyperresponsiveness. The following Specific Aims will be used to test these hypotheses: 1) characterize the lung response (functional, morphological, cellular, humoral and molecular) to exposures of PM plus\minus ozone; 2) characterize the exacerbation of the lung response (functional, morphological, cellular, humoral and molecular) to exposures of PM and/or ozone in ovalbumin-sensitized mice; and 3) confirm the role of AM apoptosis, AM antigen presentation activity, as well as, Th1 and Th2 pathways in the regulation of lung inflammation caused by exposures to PM and/or ozone. Consequently, it will be possible to define the immune alterations caused by PM plus\minus ozone and the requirements of different steps in the hypothesized pathway (AM apoptosis greater than increased APC activity greater than activation of Th2 pathway) leading to airway hyperresponsiveness caused by PM plus\minus ozone. These studies will be most effectively conducted using the murine models described in this application and then extrapolated to humans, since similar studies can not be directly performed in humans. Furthermore, the information obtained from these studies will significantly improve our understanding of the role of the various immune cells in the regulation of lung inflammation and characterize the mechanisms by which ozone and PM mediate lung inflammation. In addition, this information may be ultimately used in improving prevention and treatment for asthma..