Airway inflammation plays a fundamental role in asthma and several other diseases of the airways. Although airway hyperresponsiveness, edema, and the presence of granulocytes are central features of asthma, their underlying mechanisms and relationship to the development of the disease are unknown. Airway hyperresponsiveness and edema have been observed in human subjects exposed to various inflammatory stimuli such as viral infection, ozone, and allergens. This proposal will use physiological, biochemical, and morphological methods to examine the mechanisms underlying airway smooth muscle hyperresponsiveness and increased airway vascular permeability following exposure to an inhaled inflammatory stimulus. Previous work suggests that both airway hyperresponsiveness and increased vascular permeability are dependent on the presence of extravascular polymorphonuclear leukocytes (PMNs) in the airways. This proposal will first examine which chemoattractants are responsible for bringing PMNs to the site of airway injury. Animals either 1) depleted of complement, 2) treated with an inhibitor of the activation of the fifth component of complement, or 3) congenitally deficient in specific complement components will be examined for increases in airway responsiveness, vascular permeability, and inflammatory cell influx following exposure to an inflammatory stimulus. To examine the role of lipoxygenase products of arachidonic acid metabolism, these same indices of airway inflammation and dysfunction will be examined in guinea pigs treated with inhibitors of lipoxygenase activity or a monoclonal antibody to LTB4. The source and nature of chemotactic factors will also be studied in isolated cells and tissues in vitro. The second portion of this proposal will determine whether various oxygen reduction species produced by PMNs are responsible for the observed increases in airway responsiveness and airway vascular permeability. Guinea pigs will be treated with selective scavengers or promoters of superoxide anion, hydrogen peroxide, and hydroxyl radical to determine which products of activated PMNs may be responsible for the inflammatory airway damage. In summary, the proposed studies may lead to a better understanding and treatment of inflammatory airway diseases by clarifying the role of PMNs in the control of airway responsiveness and vascular permeability.
