Abstract
Mice lacking surfactant protein A (SP-A) are susceptible to bacterial infection associated with an excessive inflammatory response in the lung. To determine mechanisms by which SP-A is antiinflammatory in the lung during bacterial infection, SP-A regulation of secretory leukoprotease inhibitor (SLPI), an inhibitor of serine proteases, was assessed. SLPI protein expression and antineutrophil elastase activity were reduced in bronchoalveolar fluid of SP-A(-/-) compared with SP-A(+/+) mice. Intratracheal administration of SP-A to SP-A(-/-) mice enhanced SLPI protein expression and antineutrophil elastase activity in the lung. SLPI mRNA was similar in whole lung and alveolar type II cells; however, it was significantly reduced in alveolar macrophages from SP-A(-/-) compared with SP-A(+/+) mice. In vitro, SP-A enhanced SLPI production by macrophage THP-1 cells but not respiratory epithelial A549 cells. SP-A inhibited LPS induced IkappaB-alpha degradation in THP-1 cells, which was partially reversed with knockdown of SLPI. Matrix metalloproteinase (MMP)-12 cleaved SLPI and incubation with SP-A reduced MMP-12-mediated SLPI cleavage. The collagen-like region of SP-A conferred protection of SLPI against MMP mediated cleavage. SP-A plays an important role in the lung during bacterial infection regulating protease and antiprotease activity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bronchoalveolar Lavage Fluid / chemistry
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Bronchoalveolar Lavage Fluid / immunology
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Bronchoalveolar Lavage Fluid / microbiology
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Cell Line, Tumor
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Female
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Haemophilus Infections / enzymology
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Haemophilus Infections / immunology
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Haemophilus Infections / metabolism
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Haemophilus influenzae / immunology
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Humans
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Hydrolysis
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Inflammation Mediators / metabolism
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Inflammation Mediators / physiology
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Male
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Matrix Metalloproteinase 12 / biosynthesis
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Matrix Metalloproteinase 12 / physiology*
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Matrix Metalloproteinase Inhibitors*
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Mice
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Mice, Knockout
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Pneumonia / enzymology
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Pneumonia / immunology
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Pneumonia / metabolism
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Pneumonia / pathology
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Pulmonary Surfactant-Associated Protein A / deficiency
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Pulmonary Surfactant-Associated Protein A / genetics
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Pulmonary Surfactant-Associated Protein A / physiology*
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RNA, Messenger / antagonists & inhibitors
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RNA, Messenger / biosynthesis
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Secretory Leukocyte Peptidase Inhibitor / antagonists & inhibitors
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Secretory Leukocyte Peptidase Inhibitor / biosynthesis*
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Secretory Leukocyte Peptidase Inhibitor / genetics
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Secretory Leukocyte Peptidase Inhibitor / metabolism
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Secretory Leukocyte Peptidase Inhibitor / physiology
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Up-Regulation / immunology
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alpha 1-Antitrypsin / metabolism
Substances
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Inflammation Mediators
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Matrix Metalloproteinase Inhibitors
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Pulmonary Surfactant-Associated Protein A
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RNA, Messenger
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Secretory Leukocyte Peptidase Inhibitor
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Slpi protein, mouse
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alpha 1-Antitrypsin
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Matrix Metalloproteinase 12