The lung is continually assaulted with immune challenges harbored in the 11,000 liters of air inhaled daily. Fortunately, there are innate immune systems in the lung that facilitate clearance of pathogens and modulate the inflammatory response. The goal of this proposal is to define contributions and interactions of 3 protective immune pathways in the lung: 1) surfactant, 2) complement, and 3) C-reactive protein (CRP). Surfactant is a lipoprotein complex that reduces surface tension and plays a role in host defense. Surfactant proteins, SP-A and SP-D, are important mediators of innate immunity and enhance phagocytosis and modulate cytokine production. The complement system regulates multiple immune functions including phagocytosis, recruitment of immune ceils and production of inflammatory mediators; one of the complement components, C1q, is structurally homologous to SP-A. CRP is an acute phase protein that also enhances phagocytosis and regulates complement activation. The hypothesis to be tested is that interactions of SP-A and SP-D with complement components and CRP are important in regulating lung innate immunity; these interactions result in a host response that maximizes the clearance of inhaled pathogens while minimizing the proinflammatory consequences of these cascades. The rationale is supported by the following preliminary data and studies from other labs: 1) The lung has an intact complement system that is highly regulated, in part by SP-A; 2) There are interactions between components of these 3 pathways; SP-A binds to complement component C1q, and SP-D binds to CRP; and 3) Enhanced susceptibility to infection and inflammation in mice and/or humans has been associated with deficiencies in surfactant, complement, and CRP.
Four aims are proposed; 1) Investigate the mechanism by which SP-A inhibits complement activation both in vitro and in vivo; 2) Establish if SP-D or SP-A regulate CRP-mediated complement activity in the lung; 3) Determine if SP-A or SP-D affect C1q and CRP-mediated cellular responses; and 4) Identify cellular sources of complement and CRP in the lung, determine if levels are upregulated in lung inflammation, and determine if deficiencies are associated with lung disease. An understanding of the molecular mechanisms by which these interactions occur and the functional consequences could lead to the design of novel therapies of surfactant replacement in combination with components of complement and/or CRP that would optimize treatment for inflammatory and infectious lung diseases.
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