Viruses are important causes of asthmatic exacerbations. However, the cellular and molecular events that mediate these exacerbations are poorly understood and the similarities between these processes and the events that mediate antigen-induced asthma have not been defined. Interleukin-11 is a cationic that stimulates T cells via a B cell- dependent mechanism and, is an IL-6-type cytokine, which regulate neural differentiation. Studies from our laboratory have demonstrated that human lung fibroblasts, epithelial-like cells and smooth muscle cells produce IL-11 in response to cytokines, histamine, eosinophil major basic protein, respiratory syncytial virus (RSV), rhinovirus and parainfluenza virus Type 3. They have also demonstrated that IL-11 causes peribronchial inflammation and airways hyperresponsiveness in mouse lungs, exaggerated levels of IL-11 are detectable in nasal secretions of people with viral respiratory tract infections and that transgenic over- expression of IL-11 in the lung causes peribronchial inflammation and airway remodeling with subepithelial fibrosis. As a result, we hypothesize that IL-11 is an important mediator of the pathophysiology of viral-induced asthma. To test this hypothesis we propose to: 1. Compare the expression of IL_11 in murine models of viral (RSV) and antigen-stimulated (ovalbumin and picrylchloride) airways inflammation and hyperresponsiveness. 2. Characterize the processes regulating IL-11 production in vitro and in vivo. We will: a. Define the cis-elements and trans-acting factors that mediate the stimulatory effects of RSV and cytokines on IL-11 gene transcription. b. Define the gene in the RSV genome that stimulates IL-11 protein production in vitro. c. Determine if this RSV gene stimulates IL-11 production in vivo. (3) Characterize the effector functions of IL-11 in vivo. We will: a. Characterize the histologic, immunologic and physiologic effects of IL-11 in mouse lungs. b. Characterize the effects of IL-11 neutralization on the histology, immunology and physiology of RSV infected and antigen- sensitized and stimulated mice. c. Create and characterize transgenic mice in which IL-11 is over- expressed in an airway selective/specific fashion using the CC10 promoter.
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