Role of Fungi in Asthma and Allergies
Principle Investigator: Sanjiv Sur, MD
Allergic asthma is a major cause of morbidity and mortality, but the mechanism by which some humans become sensitized to allergens is unknown. We have shown that intrinsic pollen NADPH oxidases vigorously promote allergic inflammation in sensitized mice by inducing oxidative stress in the airway epithelium. However, ongoing work indicates that these oxidases are relatively weak inducers of allergic sensitization. The airway epithelium is the first line of defense against inhaled allergens, and it acts as a powerful barrier against allergic sensitization.
The factors that alter this epithelial barrier so that it promotes sensitization are an intense area of research. Epidemiologic studies have demonstrated an association between mold exposure and allergic sensitization and asthma, suggesting that exposure to molds could be the missing factor that initiates allergic sensitization to pollens. We propose to test the hypothesis that mold-exposure injures the airway epithelium and activates ROS pathways that mediate the release of “danger cytokines” IL-18 and High mobility group box 1 (HMGB1). The latter is chromatin protein that acts as a pro-inflammatory cytokine “alarmin” when released extracellularly. These cytokines drive Th2 differentiation and promote allergic sensitization to concomitantly inhaled bystander allergens.
We will perform bronchscopy, BAL and bronchial brushing on normal subjects and patients with mild allergic asthma. We will examine differences in levels of danger cytokine released from primary airway epithelial cells derived from subjects with mild allergic asthma and those from healthy control subjects when cultured with Alternaria extract, and test the ability of these epithelial supernatants to induce Th2 responses to bystander antigens. Achieving this aim will provide preliminary data for a later fully- developed proposal. Eventually, the information from this aim is likely to be useful for developing unique strategies and inhibitors that may prevent development of allergies throughout the world, thereby reducing morbidity from allergic rhinitis and asthma.