Allergic airway disease is the result of multiple processes that include, airway inflammation and disruption of the functional epithelium. These events culminated in subepithelial fibrosis and airway narrowing. The hypothesis to be tested is that signaling pathways activated with bronchiolar epithelium are crucial to the development of inflammation, epithelial injury, repair and sub-epithelial fibrosis. We postulate that the activation of NF-kappaB is critical to the induction of inflammation, because this transcription factor controls the production of granulocyte chemokines.
In Specific Aim #1, we will determine the selectivity of NF- kappaB activation in bronchiolar epithelium as well as the expression of the NF-kappaB regulated genes, macrophage inflammatory protein 2 (MIP-2) and eotaxin. In order to determine whether the activation of NF- kappaB is required for the development of allergic airway hyperresponsiveness and fibrosis, in Specific Aim #2 we will study mice that express a dominant negative mutant of inhibitory kappa B (dn- IkappaB). We postulate that once inflammatory cells are recruited into the airways, the production of mediators, specifically cationic proteins, will cause activation of mitogen-activated protein kinases (MAPKs) and epithelial injury.
In Specific Aim #3, we will test whether cationic proteins cause activation of MAPKs in epithelial cell cultures. Using dominant negative constructed to block MAPKs, we will determine the causal involvement of MAPKs in the epithelial injury associated with exposure to cationic proteins. To determine whether the activation of MAPKs in bronchiolar epithelium are causally linked to airway remodeling and fibrosis in Specific Aim #4 we will utilize transgenic mice that express dominant negative c-Jun-N-terminal kinase-1 (dnJNK1). These investigators will allow the dissection of signaling pathways responsible for antigen-induced inflammation and subsequent airway injury, remodeling, and fibrosis.
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