Mice lacking the epithelial integrin, avpe, that we have shown activates latent TGFp, are protected from thepersistent airway hyperresponsiveness (AHR) that follows chronic allergen challenge. Surprisingly, thisprotection is not associated with any decrease in sub-epithelial airway fibrosis, a central TGFp-dependentfeature of this model. Mice Iwith leukocyte specific knockout of the related integrin, avp8, which alsoactivates TGFp show evidence of enhanced adaptive immunity. In this proposal, we will determine whetherthese altered responses in P6 subunit knockout mice are a direct consequence of loss of the avp6 integrinand/or of TGFp activation from conducting airway epithelial cells using 'rescue' mice expressing either thewild type integrin or active TGFp in airway epithelial cells. We will evaluate the effects of avpe antibodies anda TGFpRII-lg chimera on these same endpoints to further confirm the importance of this pathway andevaluate the feasibility of targeting this pathway for therapeutic intervention. To determine the mechanismsby which loss of avp6 protects from induction of AHR, we will eavluate the relationship between airwayresponsiveness and expression of a small number of candidate genes identified as linked to this phenotypein preliminary experiments utilizing expression microarrays. We will also determine the cellular distribution ofexpression by immunostaining and/or in situ hybridization, and will evaluate functional significance usingcommercially available lines of mice expressing null mutations of specific candidates. Because the cytokineIL-13 is known to play a central role in induction of AHR in multiple models, and because two of the mostpromising candidates identified by microarrays, leuotriene C4 synthase and interleukin-18 have beensuggested 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 leukocyteavp8 leads to enhancement of adaptive immunity and examine the relevance of this pathway to allergicairway inflammation and its consequences.Lay summary- This project will examine how a single growth factor, transforming growth factor p, can eithercontribute to development of chronic asthma or inhibit allergic sensitization and its consequences, dependingon where and how this growth factor is activated.
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