Bacterial pneumonia is a leading cause of morbidity and mortality in the United States. Infection is initiated by inhaled microorganisms that are deposited in the aqueous lining film which coats the alveolar epithelium. This compartment contains pulmonary surfactant, a mixture of phospholipids and proteins that maintains alveolar patency by reducing surface tension forces at the dir-liquid interface. Recent data suggests that surfactant protein A (SP-A), an abundant oligomeric glycoprotein in the distal airspaces, is also an acute phase reactant that functions as a major preimmune opsonin and lipopolysaccharide (LPs)-binding protein in the lung. The response of the alveolar macrophage (AM), the predominant inflammatory cell in the alveolar lumen, to microbes and microbial products must be tightly regulated to promote effective clearance while avoiding inappropriate inflammatory responses that may compromise gas exchange. Preliminary data presented herein suggests that SP-A enhances the clearance of pulmonary bacterial infections in mice and regulates the interaction of LPS with macrophages. Using recombinant SP-As with targeted mutations in critical structural domains and transgenic mice that overexpress rat and mutant of SP-A, we will test the hypothesis that SP-A modulates the inflammatory response of the lung to LPS and pathogenic microorganisms in the lung, and in the clearance of LPS and microbial infection from the airspace.
Specific aim #2 will examine the structural domains of SP- A that mediate binding to LPS and bacterial microorganisms, the production of proinflammatory mediators and nitric oxide, and the clearance of LPS and microorganisms from the airspace. These studies will elucidate the role of SP-A in the innate immune defense of the lung, and may assist in the design of optimal antimicrobial strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL061612-01
Application #
2739351
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1998-12-01
Project End
2002-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Beharka, Alison A; Crowther, Joy E; McCormack, Francis X et al. (2005) Pulmonary surfactant protein A activates a phosphatidylinositol 3-kinase/calcium signal transduction pathway in human macrophages: participation in the up-regulation of mannose receptor activity. J Immunol 175:2227-36
Schaeffer, Lyndsay M; McCormack, Francis X; Wu, Huixing et al. (2004) Interactions of pulmonary collectins with Bordetella bronchiseptica and Bordetella pertussis lipopolysaccharide elucidate the structural basis of their antimicrobial activities. Infect Immun 72:7124-30
Schaeffer, Lyndsay M; McCormack, Francis X; Wu, Huixing et al. (2004) Bordetella pertussis lipopolysaccharide resists the bactericidal effects of pulmonary surfactant protein A. J Immunol 173:1959-65
Chabot, Sophie; Salez, Laurent; McCormack, Francis X et al. (2003) Surfactant protein A inhibits lipopolysaccharide-induced in vivo production of interleukin-10 by mononuclear phagocytes during lung inflammation. Am J Respir Cell Mol Biol 28:347-53
Wu, Huixing; Kuzmenko, Alexander; Wan, Sijue et al. (2003) Surfactant proteins A and D inhibit the growth of Gram-negative bacteria by increasing membrane permeability. J Clin Invest 111:1589-602
McCormack, Francis X; Gibbons, Reta; Ward, Susan R et al. (2003) Macrophage-independent fungicidal action of the pulmonary collectins. J Biol Chem 278:36250-6
Malloy, Jaret L; Veldhuizen, Ruud A W; McCormack, Francis X et al. (2002) Pulmonary surfactant and inflammation in septic adult mice: role of surfactant protein A. J Appl Physiol 92:809-16
Beharka, Alison A; Gaynor, Cecilia D; Kang, Byoung K et al. (2002) Pulmonary surfactant protein A up-regulates activity of the mannose receptor, a pattern recognition receptor expressed on human macrophages. J Immunol 169:3565-73
Palaniyar, Nades; Zhang, Liquian; Kuzmenko, Alexander et al. (2002) The role of pulmonary collectin N-terminal domains in surfactant structure, function, and homeostasis in vivo. J Biol Chem 277:26971-9
McCormack, Francis X; Whitsett, Jeffrey A (2002) The pulmonary collectins, SP-A and SP-D, orchestrate innate immunity in the lung. J Clin Invest 109:707-12

Showing the most recent 10 out of 15 publications