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J. Biol. Chem., Vol. 277, Issue 25, 22453-22459, June 21, 2002
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From the Surfactant protein D (SP-D) and serum conglutinin
are closely related members of the collectin family of host
defense lectins. Although normally synthesized at different anatomic
sites, both proteins participate in the innate immune response
to microbial challenge. To discern the roles of specific domains
in the function of SP-D in vivo, a fusion protein
(SP-D/Congneck+CRD) consisting of the
NH2-terminal and collagenous domains of rat SP-D (rSP-D) and the neck and carbohydrate recognition domains (CRDs) of bovine conglutinin (Cong) was expressed in the respiratory epithelium of SP-D
gene-targeted (SP-D(
Complementation of Pulmonary Abnormalities in SP-D(
/) Mice
with an SP-D/Conglutinin Fusion Protein*
,, and
Division of Pulmonary Biology, Cincinnati
Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, the
§ Departments of Medicine and Pathology, Boston University
School of Medicine, Boston, Massachusetts 02118-2393, and the
¶ Department of Pathology and Immunology, Washington University
School of Medicine, St. Louis, Missouri 63110
/)) mice. While SP-D/Congneck+CRD fusion protein did not affect lung morphology and surfactant
phospholipid levels in the lungs of wild type mice, the chimeric
protein substantially corrected the increased lung phospholipids in
SP-D(/) mice. The SP-D/Congneck+CRD fusion protein also
completely corrected defects in influenza A clearance and inhibited the
exaggerated inflammatory response that occurs following viral
infection. However, the chimeric protein did not ameliorate the ongoing
lung inflammation, enhanced metalloproteinase expression, and alveolar
destruction that characterize this model of SP-D deficiency. By
contrast, a single arm mutant (RrSP-DSer15,20) partially
restored antiviral activity but otherwise failed to rescue the
deficient phenotype. Our findings directly implicate the CRDs of both
SP-D and conglutinin in host defense in vivo. Our findings
also strongly suggest that the molecular mechanisms underlying impaired
pulmonary host defense and abnormal lipid metabolism are distinct from
those that promote ongoing inflammation and the development of emphysema.
*
Supported by National Institutes of Health Grants HL63329-03
and HL61646-03 (to J. A. W. and M. I.), Grants HL29594 and HL44015 (to E. C. C.), and HL5891 (to K. L. H.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Cincinnati
Children's Hospital Medical Center, Division of Pulmonary Biology, 3333 Burnet Ave., Cincinnati, OH 45229-3039. Tel.: 513-636-4830; Fax:
513-636-7868; E-mail: jeff.whitsett@chmcc.org.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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