Surfactant protein A enhances production of secretory leukoprotease inhibitor and protects it from cleavage by matrix metalloproteinases.
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.
Ramadas
Ravisankar A
RA
Department of Pediatrics, Division of Critical Care Medicine, University of Florida, Gainesville, FL 32610, USA.
Wu
Lizhen
L
LeVine
Ann Marie
AM
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology / Q000382:microbiology; D045744:Cell Line, Tumor; D005260:Female; D006192:Haemophilus Infections / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D006193:Haemophilus influenzae / Q000276:immunology; D006801:Humans; D006868:Hydrolysis; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000096:biosynthesis / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D011014:Pneumonia / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D037662:Pulmonary Surfactant-Associated Protein A / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology; D000515:alpha 1-Antitrypsin / Q000378:metabolism
D018836:Inflammation Mediators; D061965:Matrix Metalloproteinase Inhibitors; D037662:Pulmonary Surfactant-Associated Protein A; D012333:RNA, Messenger; D053481:Secretory Leukocyte Peptidase Inhibitor; C506815:Slpi protein, mouse; D000515:alpha 1-Antitrypsin; D053508:Matrix Metalloproteinase 12