Mice lacking the epithelial integrin, avpe, that we have shown activates latent TGFp, are protected from the persistent airway hyperresponsiveness (AHR) that follows chronic allergen challenge. Surprisingly, this protection is not associated with any decrease in sub-epithelial airway fibrosis, a central TGFp-dependent feature of this model. Mice Iwith leukocyte specific knockout of the related integrin, avp8, which also activates TGFp show evidence of enhanced adaptive immunity. In this proposal, we will determine whether these altered responses in P6 subunit knockout mice are a direct consequence of loss of the avp6 integrin and/or of TGFp activation from conducting airway epithelial cells using """"""""rescue"""""""" mice expressing either the wild type integrin or active TGFp in airway epithelial cells. We will evaluate the effects of avpe antibodies and a TGFpRII-lg chimera on these same endpoints to further confirm the importance of this pathway and evaluate the feasibility of targeting this pathway for therapeutic intervention. To determine the mechanisms by which loss of avp6 protects from induction of AHR, we will eavluate the relationship between airway responsiveness and expression of a small number of candidate genes identified as linked to this phenotype in preliminary experiments utilizing expression microarrays. We will also determine the cellular distribution of expression by immunostaining and/or in situ hybridization, and will evaluate functional significance using commercially available lines of mice expressing null mutations of specific candidates. Because the cytokine IL-13 is known to play a central role in induction of AHR in multiple models, and because two of the most promising candidates identified by microarrays, leuotriene C4 synthase and interleukin-18 have been suggested to be upstream of IL-13 induction in the airways, we willl also examine the cellular sources of IL- 13 in chronically challenged wild type and P6 knockout mice. Finally, we will determine how loss of leukocyte avp8 leads to enhancement of adaptive immunity and examine the relevance of this pathway to allergic airway inflammation and its consequences. Lay summary- This project will examine how a single growth factor, transforming growth factor p, can either contribute to development of chronic asthma or inhibit allergic sensitization and its consequences, depending on where and how this growth factor is activated.
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