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J. Biol. Chem., Vol. 279, Issue 29, 30871-30879, July 16, 2004

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Degradation of Pulmonary Surfactant Protein D by Pseudomonas aeruginosa Elastase Abrogates Innate Immune Function^*

John F. Alcorn and Jo Rae Wright

From the Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710

The alveolar epithelium is lined by surfactant, a lipoprotein complex that both reduces surface tension and mediates several innate immune functions including bacterial aggregation, alteration of alveolar macrophage function, and regulation of bacterial clearance. Surfactant protein-D (SP-D) participates in several of these immune functions, and specifically it enhances the clearance of the pulmonary pathogen Pseudomonas aeruginosa, a common cause of morbidity and mortality in cystic fibrosis (CF) patients. P. aeruginosa secretes a variety of virulence factors including elastase, a zinc-metalloprotease, which degrades both SP-A and SP-D. Here we show that SP-D is cleaved by elastase to produce a stable 35-kDa fragment in a time-, temperature-, and dose-dependent manner. Degradation is inhibited by divalent metal cations, a metal chelator, and the elastase inhibitor, phosphoramidon. Sequencing the SP-D degradation products localized the major cleavage sites to the C-terminal lectin domain. The SP-D fragment fails to bind or aggregate bacteria that are aggregated by intact SP-D. SP-D fragment is observed when normal rat bronchoalveolar lavage (BAL) is treated with Pseudomonas aeruginosa elastase, and SP-D fragments are present in the BAL of CF lung allograft patients. These data show that degradation of SP-D occurs in the BAL environment and that degradation eliminates many normal immune functions of SP-D.

Received for publication, January 23, 2004 , and in revised form, April 30, 2004.

^* This work was supported by National Institutes of Health Grant HL-51134. 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 and reprint requests should be addressed: Dept. of Cell Biology, Box 3709, Durham, NC 27710. Tel.: 919-684-8040; Fax: 919-684-8106; E-mail: j.wright{at}cellbio.duke.edu.

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