The present proposal is based on our recent discovery that Surfactant Protein B (SP-B) exhibits anti-baterial activity. The significance of this finding is three-fold. First SP-B is native to the mammalian lung (expressed solely in the lung) and is secreted by bronchial, bronchiolar and alveolar epithelial cells at relatively high concentrations. Thus, it may act as a component of innate immunity to prevent bacterial colonization in the human lung. Second, surfactant replacement preparations distress syndromes (NRDS and ARDS). Studies have shown that use of such preparations do not elicit immunological responses. Third, SP-B is easily isolated and purified from lungs of a variety of species. Use of SP-B to prevent or eradicated bacterial growth would be of especially importance in diseases such as cystic fibrosis and bacterial pneumonia, where pathogenesis is likely to be a result of bacterial colonization and infection. We will now determine the factors that affect antibacterial activity of SP-B and will test the hypothesis that SP-B is a component of the innate immune system, protecting against bacterial colonization in nondiseased lungs, but this activity may be compromised in lungs of cystic fibrosis patients. We will determine the mechanism by which SP-B kills bacteria using site-directed mutagenesis, peptide synthesis along and structural/functional analysis. Finally, we will test the hypothesis that native SP-B, recombinant SP-B and/pr SP-B synthetic analogs can be used as antibacterial agents in vivo.
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