Transforming growth factor-beta (TGF-beta) has been strongly implicated in the development of allergic asthma. Mast cell degranulation also plays a key role in exacerbating allergic asthma, and is the therapeutic target of both leukotriene antagonists and anti-IgE antibodies. Recent data from our laboratory has suggested that mice lacking the alpha v beta6 integrin, which modulates TGF-beta activity, are protected from airway hyperreactivity. Furthermore, this effect is mediated by differential mast cell protease expression induced by TGF-beta, namely via the upregulation of mMCP-1 and the downregulation of mMCP-4. These proteases have been shown to influence airway hyperreactivity, with mMCP-1 augmenting smooth muscle contraction in response to methacholine and mMCP-4 inhibiting IL-13 induced contraction. In this proposal we will systematically investigate the mechanism by which mMCP-1 and mMCP-4 affect contractile response using parallel experimental systems (tracheal ring contraction in muscle bath and airway narrowing in lung slices). We will use constructs of mMCP-1-, and mMCP-4- knockout mice to assess what contribution the interaction of TGF-beta with mast cells makes to the contractile response. We propose to determine whether mMCP-1 and mMCP-4 act directly on smooth muscle or indirectly via adjacent epithelial cells. Since force generation in smooth muscle depends on Ca2+-dependent actin-myosin cross-bridging, we will also investigate how mMCP-1 and mMCP-4 modulate Ca2+ homeostasis. The proposed studies will elucidate the mechanism by which TGF-beta-modulated expression of mast cell proteases mMCP-1 and mMCP-4 affect airway hyperreactivity. As this pathway plays an important role in the pathogenesis of allergic asthma, a more thorough understanding will provide potential targets for future therapy.
One of the key features of allergic asthma is exaggerated airway narrowing. Mast cells in the airway release various proteases that play an important role in exacerbating allergic asthma. This research proposal will determine how the proteases secreted by mast cells work to cause exaggerated airway narrowing.
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