Adjuvant effect of a particulate matter air pollutant on pulmonary allergy: Model and mechanisms

The incidence of asthma has been increasing in the United States and other industrialized societies for the past two decades, especially in children. Epidemiological studies have shown a strong association between increased levels of fine mode, combustion source particulate matter (PM2.5) and increased daily mortality and morbidity due to respiratory diseases such as asthma. Previous studies in both humans and laboratory animals have shown an association between exposure to particulate matter air pollutants and exacerbation of pulmonary allergy (extrinsic asthma). Little is known, however, about the effect of particulate matter exposure on the sensitization phase, or the actual induction of allergic pulmonary disease. We have investigated the effects of a combustion source particle, residual oil fly ash (ROFA) on a rodent model of pulmonary allergy to a common human allergen, house dust mite (HDM). Brown Norway rats, a genetically atopic strain, were instilled via the trachea with 200mug or 1000mug ROFA particles, inert particles, or saline acidified to the pH of ROFA, three days prior to local sensitization by intratracheal (i.t.) instillation with two doses of 5mug HDM antigen. Two weeks later, animals were challenged i.t. with 10mug HDM and immunological and pulmonary function endpoints were assessed immediately after challenge, and 2 and 7 days after challenge. The main findings of these initial studies were that ROFA particles enhanced the immediate bronchoconstriction response, pulmonary eosinophilia, and antigen-specific IgE serum titers after antigen challenge compared with controls exposed to acidified saline or inert particles. Later studies revealed that the transition metals iron, vanadium, and nickel mediated this adjuvant effect, and that the increased allergic immune responses were associated with an upregulation of Th2 lymphocyte and proinflamnmatory cytokines in the lung. Exogenous administration of the pleiotropic cytokine tumor necrosis factor alpha (TNF-alpha) or experiments designed to neutralize this cytokine in vivo with monoclonal antibody indicated that TNF-alpha played an important role in the enhancement of sensitization by PM. This model provides important information on the effects of PM on asthma induction, and may be used in conjunction with human exposure studies to provide data for assessing the risk of PM exposure.