ALVEOLAR MACROPHAGE ACTIVATION BY INTEGRIN KNOCK-OUT

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Pulmonary inflammation is pivotal in many respiratory disorders including asthma, ARDS, and pulmonary fibrosis. Recent evidence suggests that the epithelial integrin alphavbeta6 may be important in pulmonary and dermal inflammation. In particular, inactivation of the beta6 subunit of the alphavbeta6 integrin in mice either by creation of a null mutant (beta6 minus/minus), or by treatment with inactivating antibody or peptide results in airway hyperresponsiveness, lymphocytic bronchiolitis, dermatitis and particularly, histological evidence of macrophage activation. Alphavbeta6 is expressed primarily on epithelial cells, unregulated in response to injury and is known to be a receptor for the extracellular matrix proteins fibronectin, tenascin, and vitronection. Macrophages secrete a wide array of cytokines which modulate the activation, recruitment and responses of other inflammatory cells, particularly lymphocytes. The observation that elimination of alphavbeta6 expression may result in alveolar macrophage activation suggests that changes in integrin expression on a surface of respiratory epithelia can result in macrophage activation either indirectly through secretion of inflammatory mediators, or through direct cell-cell interactions. These experiments will define the mechanisms of this inflammatory activation focusing on the role of alveolar macrophages and epithelial cell-macrophage interactions. Following full in vivo characterization of the activation profile of alveolar macrophages from null and wild type mice, an in vivo assay system will be developed to replicate epithelial-macrophage interactions. The in vivo and in vitro effects of inactivating antibodies and peptides, as well as the effect of the null mutation on the direct and indirect interactions between respiratory epithelia and alveolar macrophages will be examined. Ultimately these experiments will provide a better understanding of the role of integrins in pulmonary inflammation and may provide important insights into novel therapeutic strategies.