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Surfactant Protein A Enhances Production of Secretory Leukoprotease Inhibitor and Protects It from Cleavage by Matrix Metalloproteinases¹

Department of Pediatrics, Division of Critical Care Medicine, University of Florida, Gainesville, FL 32610

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 IB- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant R01 HL071522 (to A.M.L.) and the American Lung Association (to A.M.L.).

² Address correspondence and reprint requests to Dr. Ann Marie LeVine, Department of Pediatrics, Critical Care Medicine, University of Florida, 1600 SW Archer Road, RG114, Gainesville, FL 32610. E-mail address: levineam{at}peds.ufl.edu

³ Abbreviations used in this paper: SP-A, surfactant protein A; BALF, bronchoalveolar lavage fluid; CRD, carbohydrate recognition domain; MMP, matrix metalloproteinase; siRNA, small interfering RNA; SLPI, secretory leukoprotease inhibitor; SP-D, surfactant protein D.