ROLE OF SURFACTANT PROTEIN B IN INNATE AIRWAY DEFENSE

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DESCRIPTION (Applicant's Abstract): Surfactant protein B (SP-B) is essential for postnatal survival and normal surfactant function. SP-B is capable of reorganizing lipid bilayers and is fusigenic protein. Based on these characteristics and the similarity of SP-B's amino acid sequence to those of several antimicrobial peptides, we hypothesized that SP-B itself has antimicrobial properties. Preliminary data obtained by our laboratory have demonstrated he SP-B has in vitro antibacterial activity. The significance of this observation is three-fold. First SP-B is expressed solely in mammalian lungs where it is secreted into the airway lining fluid by bronchial, bronchiolar and alveolar epithelial cells at relatively high concentrations. For that reason, it may act as a component of local mucosal immunity to prevent bacterial infections in these and other regions of the lung. Second, surfactant replacement preparations containing SP-B are presently used for safe treatment of neonatal respiratory distress syndrome, and such preparations do not elicit immunological responses. Third, SP-B is easily isolated or synthesized. Thus, there is potential for safe therapeutic use of SP-B for treatment of pulmonary bacterial infections. Use of SP-B to prevent or eradicate bacterial growth in the airway would be of particular importance in cystic fibrosis (CF), where progressive lung damage occurs as a result of persistent bacterial infection. Moreover, we have found aberrant forms of SP-B in bronchoalveolar lavage (BAL) of adult CF patients and that mature SP-B may be degraded or modified. We will test the hypothesis that SP-B is a component of the innate pulmonary immune system, protecting the human airway against bacterial infection, and this activity may be compromised in the airways of CF patients. The aims of this proposal are 1) to determine molecular forms and activity of SP-B in BAL from CF patients vs. those of normal humans, 2) to delineate the sites in the airway where SP-B is found and in which it may play a defensive role, 3) to characterize the antibacterial activity of SP-B in vitro, and 4) to develop preparations containing native or synthetic SP-B for use as antibacterial agents in vivo. Results from the proposed experiments will lay the foundation for therapeutic use of SP-B for eradication of bacterial lung infections.