Low molecular haptens are import causes of occupational and other forms of asthma. They are presumed to mediate their effects via inflammatory and immune mechanisms. The pathogenetic events that mediate inflammation and functional dysregulation in hapten sensitized and exposed individuals, however, are poorly defined. To address these events we have established a model of hapten asthma using picrylchloride. In this model, appropriately sensitized and challenged mice develop late phase increases in airways resistance and nearly 100- fold increases in airway reactivity. This reactivity can be adoptively transferred to naive mice by antigen-specific populations of lymphocytes and is associated with submucosal infiltration by T cells, mononuclear cells and neutrophils. We believe that this inflammatory process mediates the functional changes that we have seen. We hypothesize that these inflammatory cells produce specific cytokines which induce the expression of a specific pattern of endothelial adhesion molecules which allows for the recruitment of inflammatory cells that mediate airway dysfunction. We propose to: 1) Characterize the inflammatory process that develops in the airway following antigen challenge and/or direct cell transfer. We will characterize the inflammatory response, the time course and location of cytokine gene expression by infiltrating and intrinsic lung cells, the pattern of endothelial adhesion molecule expression and the development of airways hyperresponsiveness (AHR). 2) Selectively interfere with the local recruitment of specific inflammatory cells to the airway by influencing cytokine responses and/or endothelial adhesion molecule expression and examine the effects of these manipulations on the development of inflammation and AHR. We will do this using cytokine receptor knock-out mice, bone marrow chimeric mice reconstituted with either wild-type or receptor deficient donor cells and mice treated with antibodies against P-selectin or a small molecule inhibitor to VCAM-1. 3) Compare the patterns and locations of cytokine adhesion molecule expression in the mouse hapten model to biopsies from human hapten- induced isocyanate asthma. The pattern and location of cytokine and adhesion molecule expression in the murine model and human tissues will be compared. The analysis of this unique model which recapitulates in mice many of the features of human asthma will allow a more precise definition of the cellular interactions leading to the development of hapten-induced asthmatic airway hyperreactivity.
Showing the most recent 10 out of 39 publications
