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J. Biol. Chem., Vol. 279, Issue 26, 27688-27698, June 25, 2004

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Neutrophil Serine Proteinases Inactivate Surfactant Protein D by Cleaving within a Conserved Subregion of the Carbohydrate Recognition Domain^*

Tim O. Hirche, Erika C. Crouch, Marcia Espinola, Thomas J. Brokelman¶, Robert P. Mecham¶, Nihal DeSilva, Jessica Cooley||, Eileen Remold-O'Donnell||, and Abderrazzaq Belaaouaj**

From the Departments of Medicine, Pathology and Immunology, ^¶Cell Biology and Physiology, and ^**Molecular Microbiology, Washington University School of Medicine, Saint Louis, Missouri 63110 and the ^||CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts 02115

Surfactant protein D (SP-D) plays important roles in innate immunity including the defense against bacteria, fungi, and respiratory viruses. Because SP-D specifically interacts with neutrophils that infiltrate the lung in response to acute inflammation and infection, we examined the hypothesis that the neutrophil-derived serine proteinases (NSPs): neutrophil elastase, proteinase-3, and cathepsin G degrade SP-D. All three human NSPs specifically cleaved recombinant rat and natural human SP-D dodecamers in a time- and dose-dependent manner, which was reciprocally dependent on calcium concentration. The NSPs generated similar, relatively stable, disulfide cross-linked immunoreactive fragments of 35 kDa (reduced), and sequencing of a major catheptic fragment definitively localized the major sites of cleavage to a highly conserved subregion of the carbohydrate recognition domain. Cleavage markedly reduced the ability of SP-D to promote bacterial aggregation and to bind to yeast mannan in vitro. Incubation of SP-D with isolated murine neutrophils led to the generation of similar fragments, and cleavage was inhibited with synthetic and natural serine proteinase inhibitors. In addition, neutrophils genetically deficient in neutrophil elastase and/or cathepsin G were impaired in their ability to degrade SP-D. Using a mouse model of acute bacterial pneumonia, we observed the accumulation of SP-D at sites of neutrophil infiltration coinciding with the appearance of 35-kDa SP-D fragments in bronchoalveolar lavage fluids. Together, our data suggest that neutrophil-derived serine proteinases cleave SP-D at sites of inflammation with potential deleterious effects on its biological functions.

Received for publication, March 16, 2004 , and in revised form, April 9, 2004.

^* This work was supported by grants from the Barnes Jewish Hospital Foundation and the Alan A. and Edith L. Wolff Charitable Trust (to A. B.), the Cystic Fibrosis Foundation (to E. R.), and National Institutes of Health Grants HL-66415 (to A. B.), HL-29594 and HL-44015 (to E. C.), and HL-66548 (to E. R.-O). 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.

To whom correspondence may be addressed: Division of Pulmonary and Critical Care Medicine, Dept. of Medicine, Washington University School of Medicine, Saint Louis, MO 63110. Tel.: 314-454-8448; Fax: 314-454-8781; E-mail: azzaq{at}im.wustl.edu.

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