Surfactant protein-D is a recently described member of the collectin family. As a family, the collectins are important pattern recognition molecules that bind microbial carbohydrates in a calcium dependent manner. Several mechanisms of enhanced microbial clearance have been demonstrated with members of this family of molecules. SP-D is expressed in alveolar epithelium and gastric mucosa in cells that are important in maintaining a phospholipid barrier to the environment. SP-D binds and agglutinates a variety of enteric and respiratory pathogens including influenza A virus, Salmonella minnesota, Escherichia coli, Cryptococcus neoformans, and Pneumocystis carinii at physiologically relevant concentrations. As a consequence of binding, several such organisms become adherent to alveolar macrophages but are not opsonized. Alveolar macrophages bind SP-D by two distinct mechanisms and SP-D is a potent chemotactic agent for both monocytes and neutrophils. in vitro experiments suggest that SP-D is an important host defense molecule for Influenza A viruses and may have a role in preventing secondary bacterial infections after influenza infection. However, a role for SP-D has not been demonstrated in vivo. It is hypothesized that SP-D has a role in regulating surfactant secretion. Since SP-D is chemotactic, SP-D may regulate the abundance of alveolar macrophages. The investigators further hypothesize that SP-D promotes clearance of respiratory pathogens in vivo and that increasing alveolar SP-D may increase resistance to specific pathogens. They propose to construct transgenic mice which carry null mutations for SP-D and to use an existing colony of mice which overexpress SP-D to test those hypotheses. They will study the mechanisms underlying these functions. Such investigations offer opportunities to better understand host resistance. A better understanding of innate immunity offers opportunities to identify individuals at risk for specific respiratory infections and to develop new therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL041320-11
Application #
2777194
Study Section
Special Emphasis Panel (ZRG2-PHY (01))
Project Start
1988-07-01
Project End
2001-12-31
Budget Start
1998-06-01
Budget End
1998-12-31
Support Year
11
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Fisher, J H; Sheftelyevich, V; Ho, Y S et al. (2000) Pulmonary-specific expression of SP-D corrects pulmonary lipid accumulation in SP-D gene-targeted mice. Am J Physiol Lung Cell Mol Physiol 278:L365-73
Wert, S E; Yoshida, M; LeVine, A M et al. (2000) Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice. Proc Natl Acad Sci U S A 97:5972-7
Korfhagen, T R; Sheftelyevich, V; Burhans, M S et al. (1998) Surfactant protein-D regulates surfactant phospholipid homeostasis in vivo. J Biol Chem 273:28438-43
Fisher, J H; Mason, R (1995) Expression of pulmonary surfactant protein D in rat gastric mucosa. Am J Respir Cell Mol Biol 12:13-8
Kinnard, W V; Tuder, R; Papst, P et al. (1994) Regulation of alveolar type II cell differentiation and proliferation in adult rat lung explants. Am J Respir Cell Mol Biol 11:416-25
Deterding, R R; Shimizu, H; Fisher, J H et al. (1994) Regulation of surfactant protein D expression by glucocorticoids in vitro and in vivo. Am J Respir Cell Mol Biol 10:30-7
Stelzner, T J; O'Brien, R F; Yanagisawa, M et al. (1992) Increased lung endothelin-1 production in rats with idiopathic pulmonary hypertension. Am J Physiol 262:L614-20
Shimizu, H; Fisher, J H; Papst, P et al. (1992) Primary structure of rat pulmonary surfactant protein D. cDNA and deduced amino acid sequence. J Biol Chem 267:1853-7
Fisher, J H; McCormack, F; Park, S S et al. (1991) In vivo regulation of surfactant proteins by glucocorticoids. Am J Respir Cell Mol Biol 5:63-70
Hendrickson, D J; Fisher, J H; Jones, C et al. (1990) Regional localization of human extracellular superoxide dismutase gene to 4pter-q21. Genomics 8:736-8

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