Pulmonary surfactant is a mixture of lipids and specific proteins that reduces surface tension at the alveolar air-liquid interace. A deficiency of surfactant, such as is often seen in premature babies suffering from respiratory distress syndrome, results in inadequate oxygenation and labored breathing. Although the most well established function of surfactant is reduction of surface tension, at least two lines of evidence suggest that surfactant proteins SP-A and SP-D may play a role in host defense against infection. First, SP-A has structural homology with the first component of the complement cascade, C1q and second, SP-A and SP-D share structural and amino acid sequence homology with a family of calcium-dependent lectins that includes the serum mannose binding protein and conglutinin, which participate in a variety of host defense mechanisms. The long term objective of this study is to investigate the potential role of SP-A and SP-D as regulators of pulmonary immune responses. The specific hypothesis to be tested is that SP-A and SP-D bind to the surface of invading organisms via a lectin-like calcium-dependent interaction. The proteins can then stimulate chemotaxis, or directed movement, of the alveolar macrophage toward the region of infection or inflammation. The interaction of SP-A and SP-D with a receptor on the macrophage (or other immunocompetent cells) leads to a cascade of events including phagocytosis, production of reactive oxygen species, alterations in levels of second messengers, and intracellular killing, which culminates in a coordinated response to the invading organisms mediated by SP-A and SP-D. This important response may be a first line of defense against a variety of inhaled pathogens which can assult the pulmonary epithelium. This hypothesis will be tested by investigating 5 specific aims.
Specific aim #1 is to characterize the binding and mechanism of the interaction of SP-A and SP-D with various pathogens.
Specific aim #2 is to determine if SP-A and SP-D have antibacterial or bactericidal activity.
Specific aim #3 is to isolate and characterize the alveolar macrophage SP-A receptor.
Specific aim #4 is to determine if alveolar macrophages express a receptor for SP-D.
Specific aim #5 is to characterize the effects of SP-A and SP-D on cellular functions including chemotaxis, phagocytosis, and to investigate the cellular specificity of these responses. These studies should provide new information relevant to surfactant therapy for both adults and infants and should help define the mechanism by which this family of calcium-dependent lectins mediates the immune response.
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