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J. Biol. Chem., Vol. 277, Issue 30, 26971-26979, July 26, 2002
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From the The N-terminal domains of the lung
collectins, surfactant proteins A (SP-A) and D (SP-D), are critical for
surfactant phospholipid interactions and surfactant homeostasis,
respectively. To further assess the importance of lung collectin
N-terminal domains in surfactant structure and function, a chimeric
SP-D/SP-A (D/A) gene was constructed by substituting nucleotides
encoding amino acids Asn1-Ala7 of rat
SP-A with the corresponding N-terminal sequences from rat SP-D,
Ala1-Asn25. Recombinant D/A migrated as a
35-kDa band on reducing SDS-PAGE and as a ladder of disulfide-linked
multimers under nonreducing conditions. The recombinant D/A bound and
aggregated phosphatidylcholine containing vesicles as effectively as
rat SP-A. Mice in which endogenous pulmonary collectins were replaced
with D/A were developed by human SP-C promoter-driven overexpression of
the D/A gene in SP-A
The Role of Pulmonary Collectin N-terminal Domains in Surfactant
Structure, Function, and Homeostasis in Vivo*
§,,,,
Division of Pulmonary/Critical Care
Medicine, Department of Medicine, University of Cincinnati School of
Medicine and the ¶ Division of Pulmonary Biology, Department of
Pediatrics, Children's Hospital Research Foundation,
Cincinnati, Ohio 45267-0564
/ and SP-D/
animals. Analysis of lavage fluid from SP-A/,D/A mice
revealed that glycosylated, oligomeric D/A was secreted into the air
spaces at levels that were comparable with the authentic collectins and
that the N-terminal interchange converted SP-A from a "bouquet" to
a cruciform configuration. Transmission electron microscopy of
surfactant from the SP-A/,D/A mice revealed atypical
tubular myelin containing central "target-like" electron density.
Surfactant isolated from SP-A/,D/A mice exhibited
elevated surface tension both in the presence and absence of plasma
inhibitors, but whole lung compliance of the SP-A/,D/A
animals was not different from the SP-A/ littermates.
Lung-specific overexpression of D/A in the SPD/ mouse
resulted in hetero-oligomer formation with mouse SP-A and did not
correct the air space dilation or phospholipidosis that occurs in the
absence of SP-D. These studies indicate that the N terminus of SP-D 1)
can functionally replace the N terminus of SP-A for lipid aggregation
and tubular myelin formation, but not for surface tension lowering
properties of SP-A, and 2) is not sufficient to reverse the structural
and metabolic pulmonary defects in the SP-D/ mouse.
*
Portions of this work were supported by the Medical Research
Service of the Department of Veterans Affairs (to F. M.);
National Institutes of Health Grants HL-61612 (to F. M.), HL-58795 (to T. K.), and HL-61646 and HL-63329 (to J. W., T. K., and M. I.); and
the American Lung Association and Medical Research Council of
Canada (to N. P.).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: P.O. Box 670564, Cincinnati, OH 45267-0564. Tel.: 513-558-0480; Fax: 513-558-4858; E-mail: frank.mccormack@uc.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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