Galectins are a protein family defined by their affinity for b-galactoside-containing sugars and consensus protein sequences. Galectin-3 has multiple functions, including chemotactic activity for monocytes, which has been demonstrated both in vitro and in vivo. This lectin also attracts eosinophils in vivo, probably through stimulation of various cell types to release eosinophil chemoattractants. Galectin-3 is expressed in airway epithelial cells and alveolar macrophages and is highly upregulated in the airways during allergic inflammation in a murine mode. Galectin-3-deficient mice develop a significantly lower level of eosinophil airway inflammation compared with wild-type mice, following airway antigen challenge. Other investigators have shown that galectin-9 is a potent eosinophil chemoattractant. In order to establish the role of galectin-3 and -9 in asthma through their chemotactic effects, we propose to: (1) detect galectin-9 in the airways and demonstrate its eosinophil chemoattractant activity in vitro. Whether galectin-9 is upregulated in the airways in asthmatic patients and represents a major eosinophil chemoattractant in BAL fluid will be determined. Whether galectin-9 can attract eosinophils when it is bound to extracellular matrix proteins, induce integrin expression, and, cause eosinophil transmigration through airway epithelial barrier will be determined; (2) establish the role of galectin-9 in asthma by using animal models. Whether administration of galectin-9 into the airways causes an eosinophil infiltration will be tested. The role of galectin-9 in eosinophilia airway inflammation will be established by using transgenic mice and specific inhibitors; (3) establish the chemotactic effect of galectin-3 in allergic airway inflammation. Whether galectin-3 is upregulated in the airways in asthmatic patients will be determined. Whether galectin-3 induces eosinophil chemokines in various cell types in vitro will be studied. The role of galectin-3 in eosinophil infiltration in the murine model of asthma will be investigated using galectin-3-deficient mice; and (4) elucidate the signaling pathways responsible for galectins? chemotactic effects. Whether galectin-3 utilizes known chemokine receptors on monocytes will be determined. Whether galectin-3's chemotactic effect is mediated through protein tyrosine kinases, in addition to G-protein-coupled receptors, and whether it involves activation of protein kinase C, phosphoinositide 3-kinase and Rho ATPases will be investigated.
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