Viruses are important causes of asthmatic exacerbations. However, the cellular and molecular events that mediate these exacerbations are poorly understood and the similarities and differences between these processes and the events that mediate antigen-induced asthma have not been defined. Interleukin-11 is a cationic cytokine that stimulates CD4+/RA(-) cells, activates B cells via a CD4+T cell-dependent mechanism and regulates 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 the nasal secretions of people with viral respiratory tract infections and that transgenic overexpression of IL-11 in the lung causes peribronchial inflammation, airway remodeling with subepithelial fibrosis, increased airways resistance and airways hyperresponsiveness to methacholine. 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 Gene(s) in the RSV Genome that stimulates IL-11 in vitro and in vivo. We will: (a) Define the gene(s) in the RSV genome that stimulates IL-11 production in vitro. (b) Determine if this RSV gene(s) stimulates IL-11 production in vivo by expressing it in a transgenic fashion using the CC10 promoter. (3) Characterize the respiratory 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 overexpressed in an airway selective/specific fashion using the CC10 promoter.
Showing the most recent 10 out of 39 publications
