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*
Children’s Hospital Medical Center, Division of Pulmonary Biology and Critical Care Medicine, Cincinnati, OH 45229; and
Division of Pulmonary Biology/Critical Care Medicine, University of Colorado, Denver, CO 80262
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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SP-A and SP-D are produced primarily by alveolar type II cells and nonciliated bronchiolar cells in the lung. SP-A binds to specific cell surface receptors on alveolar macrophages (4) and type II epithelial cells (5). In vitro, SP-A stimulates macrophage chemotaxis (6) and enhances the binding of bacteria and viruses to alveolar macrophages (3). SP-D binds to alveolar macrophages (7), binds and increases macrophage association with Escherichia coli (8), Mycobacterium tuberculosis (9), and Pneumocystis carinii (10), but does not enhance phagocytosis of these organisms in vitro. SP-D binds and increases phagocytosis of strains of Pseudomonas aeruginosa without causing bacterial aggregation (11).
Alveolar macrophages are thought to play a critical role in host defense of the lung. Alveolar macrophages bind, phagocytose, and kill bacteria in association with cellular activation, release of intracellular proteases, and reactive oxygen species. Reactive oxygen species are released by activated alveolar macrophages, directly killing bacteria. In vitro, both SP-A and SP-D can stimulate alveolar macrophages to generate oxygen radicals, measured as chemiluminescence (12, 13). Similarly, in vivo, alveolar macrophages from SP-A-deficient mice have impaired generation of reactive oxygen species (14).
Despite considerable in vitro evidence that SP-A is involved in host defense, its role in vivo has only recently been demonstrated. SP-A-deficient mice produced by targeted gene inactivation are susceptible to bacterial and viral pneumonia (15, 16). In vitro evidence supports a role of SP-D in pulmonary host defense, possibly mediated by different mechanisms than SP-A. In this study, to assess the role of SP-A and SP-D in vivo, SP-A- or SP-D-deficient mice were infected intratracheally with group B streptococcus (GBS) or Haemophilus influenzae. Microbial killing, inflammation, uptake of bacteria, and oxygen-radical generation by alveolar macrophages were compared in SP-A-/- and SP-D-/- mice in vivo.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Separate strains of mice lacking SP-A or SP-D were produced by
targeted gene inactivation. Lungs of SP-A-/- or
SP-D-/- mice do not contain detectable mRNA or
protein (15, 17). In this study, wild-type,
SP-D-/-, and SP-A-/-
mice with National Institutes of Health Swiss Black genetic background
were studied. Mice were housed and studied under Institutional Animal
Care and Use Committee-approved protocols in the animal facility of the
Children’s Hospital Research Foundation (Cincinnati, OH). Male and
female mice of 
20–25 g (35–42 days old) were used.
Preparation of bacteria
A stock culture of GBS and H. influenzae were obtained from clinical isolates provided by Dr. J. R. Wright (Department of Cell Biology, Durham, NC). Bacteria were suspended in media containing 20% glycerol and frozen in aliquots at -70°C. Bacteria from the same passage were used to minimize variations in virulence related to culture conditions. Before each experiment, an aliquot was thawed and plated on tryptic soy-5% defibrinated sheep blood agar (GBS) or chocolate agar plates (H. influenzae), inoculated into 4 ml of Todd-Hewitt (GBS) or trypticase soy (H. influenzae) broth (Difco Laboratories, Detroit, MI), and grown for 14–16 h at 37°C with continuous shaking. The broth was centrifuged, and the bacteria were washed in PBS at pH 7.2 and resuspended in 4 ml of the buffer. To facilitate studies, a growth curve was generated so the bacterial concentration could be determined spectrophotometrically and confirmed by quantitative culture of the intratracheal inoculum.
Purification of mouse SP-D
Mouse SP-D was obtained from bronchoalveolar lavage (BAL) from GM-CSF, SP-A double null mutant mice and purified by sequential affinity chromatography on maltosyl-agarose and gel filtration chromatography as described by Strong (18). Endotoxin contamination was not detected in SP-D preparations (<.06 endotoxin units/ml) using the Limulus Amoebocyte Lysate assay (Sigma, St. Louis, MO) according to manufacturer’s directions.
Labeling of bacteria with FITC and agglutination of H. influenzae and GBS with SP-D
Bacteria were grown in broth overnight as described for preparation of bacteria. The OD at 600 nm of the resulting supernatant was measured to determine bacterial concentration. The suspension was then pelleted at maximum speed in a microfuge, and the pellet was resuspended in 0.9 ml PBS, pH 7.2, and heated to 95°C for 10 min to kill the bacteria. The heat-killed bacteria were then pelleted and resuspended in 1 ml 0.1 M sodium carbonate, pH 9.0. FITC (Molecular Probes, Eugene, OR) was added as a 10 mg/ml stock in DMSO to a final concentration of 0.01 mg/ml, and the suspension was incubated for 1 h in the dark at room temperature with gentle agitation. Labeled bacteria were washed four times for 5 min each time with PBS, pH 7.2, to remove unconjugated fluorophore, and finally diluted in PBS and stored in aliquots of 100 µl at -80°C.
To examine SP-D agglutination of bacteria, equal volumes of bacterial suspension (FITC-GBS 107 CFU/ml, FITC-H. influenzae 108 CFU/ml) and SP-D (10 µg/ml) with 2 mM CaCl2 were mixed for 15 min at room temperature, centrifuged on glass slides, and examined by fluorescence microscopy. Control incubations were performed in calcium-free buffer.
Bacterial clearance
Administration of GBS (104 CFU) or H. influenzae (108 CFU) into the respiratory tract of the mice was performed by intratracheal inoculation as previously described (15). Quantitative cultures of lung homogenates were performed 6 and 24 h after inoculation of the animals with bacteria. Mice were exsanguinated after a lethal intraperitoneal injection of sodium pentobarbital. The lung was removed, weighed, and homogenized in 2 ml of sterile PBS. One hundred microliters of homogenate and further dilutions were plated on blood (GBS) or chocolate (H. influenzae) agar plates to quantitate bacteria.
Bronchoalveolar lavage
Lung cells were recovered by BAL. Animals were sacrificed as described for bacterial clearance, and lungs were lavaged three times with 1 ml of sterile PBS. The fluid was centrifuged at 800 x g for 10 min and resuspended in 1 ml of PBS. Differential cell counts were performed on cytospin preparations stained with Diff-Quick (Scientific Products, McGaw Park, IN).
Association of bacteria with alveolar macrophages
GBS and H. influenzae associated with alveolar macrophages in vivo were quantitated with light microscopy by counting the cell-associated organisms on cytospin preparations of lavage fluid 1 h after intratracheal inoculation. Organisms were scored as cell associated only if observed within the perimeter of the cells. In addition, bacterial binding and internalization by macrophages in vivo was measured by intratracheally inoculating mice with FITC-labeled GBS or H. influenzae followed by an evaluation of cell-associated fluorescence with a flow cytometer. One hour after infection, macrophages from BAL fluid were incubated in buffer (PBS, 0.2% BSA fraction V, 0.02% sodium azide) with PE-conjugated murine CD16/CD32 Abs (PharMingen, San Diego, CA) for 1 h on ice and washed two times in fresh buffer. Cell-associated fluorescence was measured on a FACScan flow cytometer, using CellQuest software (Becton Dickinson, San Jose, CA) without trypan blue. For each sample of macrophages, 20,000 cells were counted in duplicate, and the results were expressed as the percentage of macrophages with cell-associated bacteria. To discriminate between intra- and extracellular fluorescence, cells were divided into two equal aliquots, one of which was incubated in buffer containing 0.2 mg/ml of trypan blue for 3 min and the other in buffer. Trypan blue was added to quench fluorescence of extracellular FITC and eliminate fluorescence resulting from bacteria attached to the external surface of the cells.
Cytokine production
Lung homogenates were centrifuged at 800 x g, and the supernatants were stored at -20°C. TNF, IL-1ß, IL-6, and macrophage inflammatory protein (MIP)-2 were quantitated using quantitative murine sandwich ELISA kits (R&D Systems, Minneapolis, MN) according to the manufacturer’s directions. All plates were read on a microplate reader (Molecular Devices, Menlo Park, CA) and analyzed with the use of a computer-assisted analysis program (Softmax; Molecular Devices). Only assays having standard curves with a calculated regression line value >0.95 were accepted for analysis.
BAL nitrite
Nitrite in BAL fluid was measured by the Griess reaction using a commercially available assay (Bioxytech NO Assay; OXIS International, Portland, OR). Methods followed the manufacturer’s recommendations. The OD at 550 nm (OD550) was measured using a Spectramax 250 microplate reader (Molecular Devices, Sunnyvale, CA). Nitrite concentrations were calculated by comparison with the OD550 of standard solutions of sodium nitrite.
Superoxide and hydrogen peroxide generation
Superoxide anion and hydrogen peroxide
(H2O2) production by
alveolar macrophages was determined as described (14).
Eighteen hours after intratracheal inoculation of GBS
(104 CFU), alveolar macrophages were collected by
BAL with 1 ml of dye-free RPMI media (Life Technologies, Grand Island,
NY) times three. BAL fluid from eight mice was pooled to provide
sufficient numbers of macrophages for analysis. The lavage was
centrifuged at 800 x g for 10 min, and the pellet was
resuspended in 200 µl of PBS. Differential analysis of the cells
revealed >95% macrophages. One hundred thousand cells were placed in
wells of a 96-well plate with 1.2 mg/ml (100 µmol/L) cytochrome
c, with or without 20 µg/ml superoxide dismutase, in a
final volume of 200 µl of HBSS. Superoxide anion production was
determined after activation with 100 ng/ml PMA. OD at 550 nm was
determined using a THERMOmax microplate reader (Molecular Devices)
linked to a laboratory computer. Measurements were made initially, 5,
10, and 15 min, then every 15 min until 2 h at 37°C. OD was
converted to nanomoles of cytochrome c reduced using a molar
extinction coefficient of 21.1
mM-1cm-1. Each
measurement was the mean of at least two replicates with eight
determinations at each time. Data were expressed as nanomoles
cytochrome c reduced per 1 x 105
cells. Superoxide production was assessed by subtracting activity in
the presence of superoxide dismutase from total oxygen radical
production. Hydrogen peroxide production by macrophages was measured
using a commercially available assay (Bioxytech
H2O2 -560 assay; OXIS
International) based on the oxidation of ferrous ions
(Fe2+) to ferric ions
(Fe3+) by hydrogen peroxide. Ferric ions bind
with the indicator dye, xylenol orange, which was measured at 560 nm.
Sorbitol was added to the reaction to scavenge oxyl radicals and
convert them to hydrogen peroxide and hydroperoxyl radicals, increasing
the yield of ferric ions to 15 moles per mole
H2O2.
Western blot
Western blot analysis for SP-A and SP-D was performed on tissue homogenates. Lung tissue was homogenized in (500 µl) PBS to which was added 3.5 ml of 10 mM Tris-Cl (pH 7.4), 0.25 M sucrose, 2 mM EDTA, 1 mM PMSF, 10 µM leupeptin, and 10 µM pepstatin A. The homogenate was centrifuged at 250 x g for 10 min at 2°C, and the supernatant was centrifuged at 120,000 x g for 18 h. The pellet was resuspended in the above buffer (without sucrose) and subjected to SDS-PAGE on 10–27% gradient gels. Proteins were transblotted to polyvinylidene difluoride membranes (Bio-Rad, Hercules, CA) and blocked with TBST containing 5% BSA. SP-A and SP-D were detected with guinea pig anti-rat SP-A serum and rabbit anti-rat SP-D serum (the latter provided by Dr. E. Crouch, Department of Pathology, Barnes Jewish Hospital of St. Louis, Washington University, St. Louis, MO) using HRP-conjugated secondary Ab (Calbiochem, San Diego, CA). Membranes were rinsed and developed using enhanced chemiluminescence detection reagents (Amersham, Arlington Heights, IL). Immunoreactive bands were identified by exposing the membranes to XAR film (Kodak, Rochester, NY).
Statistical methods
Lung colony counts, total cell counts, cytokines, superoxide, and hydrogen peroxide were compared using the median scores nonparametric test. Findings were considered statistically significant at probability levels <0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The intratracheal dose of GBS for study (104 CFU) was determined based on previous studies (15). To determine an appropriate dose of H. influenzae, wild-type mice were inoculated intratracheally with H. influenzae at concentrations of 104-108 CFU (4 mice/group). The 108 CFU dose resulted in 50% mortality, deaths occurring after 48 h. Intratracheal administration of bacteria was well-tolerated and all animals survived the 24-h study period at these doses.
In SP-A-/- mice, increased numbers of cells
were observed in BAL fluid 6 h after GBS and 6 and 24 h after
H. influenzae infection (Fig. 1
). Likewise, cell counts in BAL fluid
were increased in SP-D-/- mice 6 h after
GBS and 24 h after H. influenzae infection compared
with wild-type mice. A significantly greater percentage of
polymorphonuclear leukocytes was detected in BAL fluid from
SP-A-/- compared with wild-type mice 24 h
after H. influenzae infection (Fig. 2). Cell differentials were not different
for SP-D-/- and wild-type mice infected with
H. influenzae or among the groups with GBS infection.
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SP-D (10 µg/ml) agglutinated FITC-labeled GBS and H.
influenzae in a calcium-dependent manner (Fig. 3). No agglutination was observed in the
absence of calcium or SP-D. Previous studies demonstrated that SP-A
binds to GBS (14) and H. influenzae
(19).
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Numbers of GBS and H. influenzae were increased in
SP-A-/- compared with wild-type and
SP-D-/- mice. The difference in bacterial
counts between SP-A-/- and wild-type mice was
most evident 6 h after infection, indicating that bacteria were
killed in the lungs of SP-A-/- mice at a slower
rate than from the lungs of wild-type mice.
SP-D-/- mice killed GBS and H.
influenzae as efficiently as wild-type mice (Fig. 4).
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Numbers of bacteria associated with alveolar macrophages, assessed
by light microscopy, were decreased in SP-A-/-
and SP-D-/- mice 1 h after
infection with GBS and H. influenzae compared with wild-type
mice (Fig. 5). Similarly, the number of
GBS and H. influenzae associated with alveolar macrophages,
assessed by flow cytometry, were significantly less in
SP-D-/- and SP-A-/-
than in wild-type mice (Fig. 5). In the presence of trypan blue, which
quenches extracellular fluorescence from surface-bound bacteria, the
percentage of intracellular GBS was similar in
SP-D-/- and wild-type macrophages (13.3 ±
1.7 vs 14.7 ± 1.3%, respectively, mean ± SEM). SP-D
increased the association of GBS with alveolar macrophages but did not
alter phagocytosis. In contrast, the number of H. influenzae
internalized by alveolar macrophages was significantly less in
SP-D-/- and SP-A-/-
than in wild-type mice, suggesting that macrophage phagocytosis of
H. influenzae was impaired in the absence of SP-D or
SP-A (Fig. 5B).
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Infection with GBS and H. influenzae significantly
increased the proinflammatory cytokines, TNF, IL-1ß, IL-6, and MIP-2
in lung homogenates from SP-A-/-,
SP-D-/-, and wild-type mice. Six hours after
infection with GBS and H. influenzae, levels of TNF and IL-6
were significantly greater in lung homogenates from
SP-A-/- and
SP-D-/- compared with wild-type mice (Fig. 6). IL-1ß was increased after H.
influenzae infection in lung homogenates from
SP-A-/- and SP-D-/-
mice. MIP-2, a neutrophil chemoattractant, was significantly greater in
lung homogenates from SP-A-/- but not
SP-D-/- mice after H. influenzae
infection. Basal cytokine levels in the lungs of control mice
inoculated with sterile PBS were low/absent and not different among
SP-A-/-, SP-D-/-, and
wild-type mice (data not shown).
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NO production after GBS and H. influenzae infection was
estimated as nitrite in BAL fluid. NO reacts with superoxide to form
peroxynitrite, which is a potent bactericidal radical. Compared with
wild-type mice, BAL fluid from SP-D-/- mice had
increased nitrite levels 6 and 24 h after GBS and H.
influenzae infection (Fig. 7).
Similarly, increased nitrite levels were observed in BAL fluid from
SP-A-/- mice 24 h after GBS and 6 and
24 h after H. influenzae infection. Baseline nitrite
levels in BAL fluid after PBS treatment were 2.4 ± 0.2, 2.8
± 0.2, and 2.7 ± 0.1 µM for wild-type,
SP-D-/-, and SP-A-/-
mice, respectively, mean ± SEM.
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Superoxide and hydrogen peroxide production were assessed in
macrophages isolated from BAL fluid 18 h after intratracheal
administration of GBS (104 CFU). After
stimulation with PMA, superoxide radical and hydrogen peroxide
production by alveolar macrophages were significantly decreased in
SP-A-/- and increased in
SP-D-/- compared with wild-type mice (Fig. 8). Macrophage hydrogen peroxide
production from PBS-treated controls was greater for
SP-D-/- compared with wild-type mice (25.5
± 5.0* and 3.4 ± 0.3 µM, respectively, mean ± SEM, with
n = 4 determinants/group; *p < 0.05
compared with wild type mice).
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Western blot analysis was used to assess whether SP-D or SP-A changed following GBS or H. influenzae infection. SP-D was not detected in SP-D-/- mice but was detected in lung homogenates from both wild-type and SP-A-/- mice; concentrations of SP-D did not change 24 h after GBS or H. influenzae infection in SP-A-/- mice (data not shown). As expected, SP-A was not detected in homogenates of the SP-A-/- mice. Similarly, SP-A was detected in lung homogenates from both wild-type and SP-D-/- mice and was not changed 24 h after GBS or H. influenzae infection in SP-D-/- mice (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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SP-A and SP-D are members of the C-type lectin family of polypeptides that includes mannose binding lectin and conglutinin. C-type lectins share structural features including collagenous amino-terminal and "globular" carboxy-terminal domains, the latter serving as a carbohydrate recognition domain that functions in opsonization. In the presence of calcium, SP-A binds to a variety of monosaccharides including mannose, fucose, glucose, and galactose. Likewise, SP-D binds complex carbohydrates but with affinities that are distinct from SP-A; SP-D binding maltose, glucose, and mannose (2). The polysaccharide capsule of GBS and H. influenzae consists of repeating monosaccharides that are likely recognized by the carbohydrate recognition domain of SP-A or SP-D. In this study, SP-D agglutinated both GBS and H. influenzae in the presence of calcium, and previous studies demonstrated SP-A binding to GBS (14).
Binding and uptake of H. influenzae by alveolar macrophages was decreased in SP-D-/- mice. However, SP-D did not enhance macrophage phagocytosis of H. influenzae in vitro (11). Macrophages from SP-D-/- mice had less cell-associated (bound and internalized) GBS, however, phagocytosis of the GBS was similar to wild-type macrophages. Macrophages from SP-D-/- mice are lipid laden, which may affect the ability to phagocytose bacteria (17). SP-D may agglutinate and bind various bacteria but may be more selective in functioning as an opsonin to enhance phagocytosis. In vitro, SP-D enhanced macrophage association with E. coli (8), Mycobacterium tuberculosis (9), and Pneumocystis carinii (10) but did not enhance phagocytosis. In contrast, SP-D enhanced phagocytosis of three of six strains of P. aeruginosa by alveolar macrophages, suggesting that SP-D-mediated phagocytosis is bacterial strain-specific. Interestingly, SP-D did not enhance aggregation of P. aeruginosa despite enhancing phagocytosis (11). SP-D aggregates bacteria, perhaps facilitating mucociliary clearance and preventing microbial adherence, invasion, and colonization of the airway/alveolar epithelium, thus enhancing host defense independent of phagocytosis.
After bacterial infection, neutrophil accumulation was similar in the lungs of the SP-D-/- and wild-type mice. In vitro, SP-D is chemotactic for neutrophils (20), and enhanced uptake of bacteria, including E. coli, S. pneumoniae, and S. aureus by neutrophils (21). However, this study demonstrates that SP-D is not a critical determinant of neutrophil chemotaxis or killing because bacterial clearance was not impaired in the absence of SP-D. These data suggest fundamental differences in SP-D effects on macrophages and neutrophils but these effects may be bacterial strain-dependent.
After bacterial infection, markers of inflammation, including inflammatory cells, cytokines, and nitrite, were increased in the lungs of SP-D-/- mice. SP-D-/- mice are able to mount an immune response to bacterial infection; however, the response is greatly increased compared with wild-type controls. NO reacts with superoxide to form peroxynitrite, which is a potent bactericidal radical. This study demonstrated increased nitrite concentration in BAL fluid from SP-D-/- mice after GBS and H. influenzae infection, which may contribute to microbial killing in combination with elevated superoxide and hydrogen peroxide in the lung. Increased cytokine production may reflect increased cells in BAL fluid after bacterial infection. Uninfected SP-D-/- mice have increased numbers of alveolar macrophages in the lung; however, proinflammatory cytokine concentrations are not increased. The results of this study demonstrate that despite efficient bacterial killing in SP-D-/- mice, intratracheal inoculation of bacteria still stimulates an inflammatory response. Thus, effects of SP-D on inflammatory responses are not dependent on bacterial proliferation.
Oxygen radical production by alveolar macrophages was increased in SP-D-/- mice. However, SP-D enhanced lucigenin-dependent chemiluminescence of rat alveolar macrophages in vitro, and this response was not inhibited by surfactant lipids (13). Because phospholipids are increased in the lungs of SP-D-/- mice, the lipid excess may inhibit the neutrophil respiratory burst as demonstrated in vitro (22). However, in this study, oxygen radical production by macrophages was increased in the absence of SP-D in vivo with and without bacterial stimulation. SP-D-/- mice have increased numbers of enlarged, foamy macrophages in the alveolar space, develop emphysema, and have abnormalities in phospholipid metabolism (17). Thus, it is difficult to determine from these studies whether the increased oxygen radical production by the macrophages from the SP-D-/- mice is a direct effect of the lack of SP-D or a result of abnormalities in surfactant metabolism that may activate alveolar macrophages.
Phagocytosis of H. influenzae by alveolar macrophages was decreased in the absence of SP-A, findings similar to previous in vivo studies with GBS (14). In vitro, SP-A bound GBS (14) and H. influenzae (19) in a calcium-dependent manner, suggesting that SP-A acts as an opsonin for these organisms. SP-A bound to S. aureus and S. pneumoniae in vitro and increased adherence of S. aureus to alveolar macrophages (23). Thus binding of SP-A to carbohydrate recognition sites on the surface of bacteria may play an important role in the early clearance of bacteria from the lungs.
After bacterial infection, markers of inflammation, including inflammatory cells, cytokines, and nitrite were increased in the lung of SP-A-/- mice, supporting previous in vivo studies with P. aeruginosa (24) respiratory syncytial viral (16) and adenoviral infection (25). McIntosh (26) reported that SP-A blunted TNF release from LPS-stimulated macrophages. This finding, that cytokine production was more robust in SP-A-/- than in wild-type mice, in vivo, supports the McIntosh study, suggesting that SP-A decreases the release of cytokines in response to bacterial infection. It is unclear from this study whether these differences are directly related to the absence of SP-A or to the increased severity of infection and failure of early bacterial clearance in the SP-A-/- mice.
Oxidant production was distinct in SP-A-/- vs SP-D-/- mice. Following bacterial infection, oxygen radical production by alveolar macrophages was decreased in SP-A-/- mice and increased in SP-D-/- mice compared with controls. Previous studies demonstrated that oxygen radical production by macrophages is impaired in the absence of SP-A in vivo (14) and SP-A enhanced lucigenin-dependent chemiluminescence of rat alveolar macrophages in vitro (12). Bacterial burden of H. influenzae was greater in the lung of the SP-A-/- mice; however, SP-D-/- mice were able to efficiently kill the bacteria. SP-A and SP-D bind and agglutinate GBS and H. influenzae (14, 19); however, clearance was impaired only in the absence of SP-A. Differences in bacterial clearance in SP-A-/- mice may be related to the impaired oxygen radical production by macrophages in the absence of SP-A. The finding that nitrite was increased following infection in both SP-A-/- and SP-D-/- mice suggests that nitrite alone is not sufficient for bacterial killing. The finding that bacterial killing was similar for SP-D-/- and wild-type mice was surprising because binding and opsonization of the bacteria were deficient in the SP-D-/- mice. However, increased numbers of macrophages and reactive oxygen species in SP-D-/- mice may compensate for the defect in opsonization.
In summary, in the absence of SP-D, bacterial killing in vivo was unchanged; however, lung inflammation was more severe in SP-D-/- and SP-A-/- mice, suggesting that SP-D and SP-A play roles in modulating cytokine production and inflammatory responses during bacterial pneumonia. In addition, SP-D and SP-A bind and agglutinate bacteria, which may, in part, enhance bacterial removal from the lung through mucociliary and macrophage clearance. Because the airway is the usual portal of entry for GBS, H. influenzae, and other respiratory pathogens, the local production of SP-A and SP-D is likely to play a role in innate defense responses to inhaled bacteria.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Ann Marie LeVine, Children’s Hospital Medical Center, Division of Pulmonary Biology, 3333 Burnet Avenue, Cincinnati, OH 45229-3039.
3 Abbreviations used in this paper: SP, surfactant protein; GBS, group B streptococcus; MIP, macrophage inflammatory protein; BAL, bronchoalveolar lavage.
Received for publication March 27, 2000. Accepted for publication July 14, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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activity from LPS-stimulated macrophages. Am. J. Physiol. 271:L310.This article has been cited by other articles:
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 S. Hansen, B. Lo, K. Evans, P. Neophytou, U. Holmskov, and J. R. Wright Surfactant Protein D Augments Bacterial Association but Attenuates Major Histocompatibility Complex Class II Presentation of Bacterial Antigens Am. J. Respir. Cell Mol. Biol., January 1, 2007; 36(1): 94 - 102. [Abstract] [Full Text] [PDF]
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J. S. Ferguson, J. L. Martin, A. K. Azad, T. R. McCarthy, P. B. Kang, D. R. Voelker, E. C. Crouch, and L. S. Schlesinger Surfactant Protein D Increases Fusion of Mycobacterium tuberculosis- Containing Phagosomes with Lysosomes in Human Macrophages Infect. Immun., December 1, 2006; 74(12): 7005 - 7009. [Abstract] [Full Text] [PDF]
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P. M. Lin and J. R. Wright Surfactant protein A binds to IgG and enhances phagocytosis of IgG-opsonized erythrocytes. Am J Physiol Lung Cell Mol Physiol, December 1, 2006; 291(6): L1199 - L1206. [Abstract] [Full Text] [PDF]
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T. C. Bailey, A. A. Maruscak, A. Petersen, S. White, J. F. Lewis, and R. A. W. Veldhuizen Physiological effects of oxidized exogenous surfactant in vivo: effects of high tidal volume and surfactant protein A Am J Physiol Lung Cell Mol Physiol, October 1, 2006; 291(4): L703 - L709. [Abstract] [Full Text] [PDF]
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P. S. Kingma, L. Zhang, M. Ikegami, K. Hartshorn, F. X. McCormack, and J. A. Whitsett Correction of Pulmonary Abnormalities in Sftpd-/- Mice Requires the Collagenous Domain of Surfactant Protein D J. Biol. Chem., August 25, 2006; 281(34): 24496 - 24505. [Abstract] [Full Text] [PDF]
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M. Lekkala, A. M. LeVine, M. J. Linke, E. C. Crouch, B. Linders, E. Brummer, and D. A. Stevens Effect of Lung Surfactant Collectins on Bronchoalveolar Macrophage Interaction with Blastomyces dermatitidis: Inhibition of Tumor Necrosis Factor Alpha Production by Surfactant Protein D. Infect. Immun., August 1, 2006; 74(8): 4549 - 4556. [Abstract] [Full Text] [PDF]
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D. A. Fraser, S. S. Bohlson, N. Jasinskiene, N. Rawal, G. Palmarini, S. Ruiz, R. Rochford, and A. J. Tenner C1q and MBL, components of the innate immune system, influence monocyte cytokine expression J. Leukoc. Biol., July 1, 2006; 80(1): 107 - 116. [Abstract] [Full Text] [PDF]
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P. Henneke and R. Berner Interaction of neonatal phagocytes with group B streptococcus: recognition and response. Infect. Immun., June 1, 2006; 74(6): 3085 - 3095. [Full Text] [PDF]
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L. Hall-Stoodley, G. Watts, J. E. Crowther, A. Balagopal, J. B. Torrelles, J. Robison-Cox, R. F. Bargatze, A. G. Harmsen, E. C. Crouch, and L. S. Schlesinger Mycobacterium tuberculosis Binding to Human Surfactant Proteins A and D, Fibronectin, and Small Airway Epithelial Cells under Shear Conditions. Infect. Immun., June 1, 2006; 74(6): 3587 - 3596. [Abstract] [Full Text] [PDF]
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E. Giannoni, T. Sawa, L. Allen, J. Wiener-Kronish, and S. Hawgood Surfactant Proteins A and D Enhance Pulmonary Clearance of Pseudomonas aeruginosa Am. J. Respir. Cell Mol. Biol., June 1, 2006; 34(6): 704 - 710. [Abstract] [Full Text] [PDF]
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A. Haczku, Y. Cao, G. Vass, S. Kierstein, P. Nath, E. N. Atochina-Vasserman, S. T. Scanlon, L. Li, D. E. Griswold, K. F. Chung, et al. IL-4 and IL-13 Form a Negative Feedback Circuit with Surfactant Protein-D in the Allergic Airway Response J. Immunol., March 15, 2006; 176(6): 3557 - 3565. [Abstract] [Full Text] [PDF]
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 A. P. Moran, W. Khamri, M. M. Walker, and M. R. Thursz Role of surfactant protein D (SP-D) in innate immunity in the gastric mucosa: evidence of interaction with Helicobacter pylori lipopolysaccharide Innate Immunity, December 1, 2005; 11(6): 357 - 362. [Abstract] [PDF]
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 H.-M. Lee, I.-H. Park, J.-S. Woo, S. W. Chae, H. J. Kang, and S. J. Hwang Up-regulation of Surfactant Protein A in Chronic Sialadenitis Arch Otolaryngol Head Neck Surg, December 1, 2005; 131(12): 1108 - 1111. [Abstract] [Full Text] [PDF]
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J. L. Alcorn, J. M. Stark, C. L. Chiappetta, G. Jenkins, and G. N. Colasurdo Effects of RSV infection on pulmonary surfactant protein SP-A in cultured human type II cells: contrasting consequences on SP-A mRNA and protein Am J Physiol Lung Cell Mol Physiol, December 1, 2005; 289(6): L1113 - L1122. [Abstract] [Full Text] [PDF]
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C.-H. Yang, J. Szeliga, J. Jordan, S. Faske, Z. Sever-Chroneos, B. Dorsett, R. E. Christian, R. E. Settlage, J. Shabanowitz, D. F. Hunt, et al. Identification of the Surfactant Protein A Receptor 210 as the Unconventional Myosin 18A J. Biol. Chem., October 14, 2005; 280(41): 34447 - 34457. [Abstract] [Full Text] [PDF]
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 J. Casey, J. Kaplan, E. N. Atochina-Vasserman, A. J. Gow, H. Kadire, Y. Tomer, J. H. Fisher, S. Hawgood, R. C. Savani, and M. F. Beers Alveolar Surfactant Protein D Content Modulates Bleomycin-induced Lung Injury Am. J. Respir. Crit. Care Med., October 1, 2005; 172(7): 869 - 877. [Abstract] [Full Text] [PDF]
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A. P. Senft, T. R. Korfhagen, J. A. Whitsett, S. D. Shapiro, and A. M. LeVine Surfactant Protein-D Regulates Soluble CD14 through Matrix Metalloproteinase-12 J. Immunol., April 15, 2005; 174(8): 4953 - 4959. [Abstract] [Full Text] [PDF]
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M. Ni, D. J. Evans, S. Hawgood, E. M. Anders, R. A. Sack, and S. M. J. Fleiszig Surfactant Protein D Is Present in Human Tear Fluid and the Cornea and Inhibits Epithelial Cell Invasion by Pseudomonas aeruginosa Infect. Immun., April 1, 2005; 73(4): 2147 - 2156. [Abstract] [Full Text] [PDF]
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F. Sanchez-Barbero, J. Strassner, R. Garcia-Canero, W. Steinhilber, and C. Casals Role of the Degree of Oligomerization in the Structure and Function of Human Surfactant Protein A J. Biol. Chem., March 4, 2005; 280(9): 7659 - 7670. [Abstract] [Full Text] [PDF]
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R. Leth-Larsen, P. Garred, H. Jensenius, J. Meschi, K. Hartshorn, J. Madsen, I. Tornoe, H. O. Madsen, G. Sorensen, E. Crouch, et al. A Common Polymorphism in the SFTPD Gene Influences Assembly, Function, and Concentration of Surfactant Protein D J. Immunol., February 1, 2005; 174(3): 1532 - 1538. [Abstract] [Full Text] [PDF]
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J. L. Malloy, R. A. W. Veldhuizen, B. A. Thibodeaux, R. J. O'Callaghan, and J. R. Wright Pseudomonas aeruginosa protease IV degrades surfactant proteins and inhibits surfactant host defense and biophysical functions Am J Physiol Lung Cell Mol Physiol, February 1, 2005; 288(2): L409 - L418. [Abstract] [Full Text] [PDF]
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A. N. Mikerov, T. M. Umstead, W. Huang, W. Liu, D. S. Phelps, and J. Floros SP-A1 and SP-A2 variants differentially enhance association of Pseudomonas aeruginosa with rat alveolar macrophages Am J Physiol Lung Cell Mol Physiol, January 1, 2005; 288(1): L150 - L158. [Abstract] [Full Text] [PDF]
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L. M. Schaeffer, F. X. McCormack, H. Wu, and A. A. Weiss Interactions of Pulmonary Collectins with Bordetella bronchiseptica and Bordetella pertussis Lipopolysaccharide Elucidate the Structural Basis of Their Antimicrobial Activities Infect. Immun., December 1, 2004; 72(12): 7124 - 7130. [Abstract] [Full Text] [PDF]
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 R. P. Schleimer Glucocorticoids Suppress Inflammation but Spare Innate Immune Responses in Airway Epithelium Proceedings of the ATS, November 1, 2004; 1(3): 222 - 230. [Abstract] [Full Text] [PDF]
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M. Griese, R. Essl, R. Schmidt, E. Rietschel, F. Ratjen, M. Ballmann, K. Paul, and for the BEAT Study Group Pulmonary Surfactant, Lung Function, and Endobronchial Inflammation in Cystic Fibrosis Am. J. Respir. Crit. Care Med., November 1, 2004; 170(9): 1000 - 1005. [Abstract] [Full Text] [PDF]
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V. Dave, T. Childs, and J. A. Whitsett Nuclear Factor of Activated T Cells Regulates Transcription of the Surfactant Protein D Gene (Sftpd) via Direct Interaction with Thyroid Transcription Factor-1 in Lung Epithelial Cells J. Biol. Chem., August 13, 2004; 279(33): 34578 - 34588. [Abstract] [Full Text] [PDF]
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A. M. LeVine, J. Elliott, J. A. Whitsett, A. Srikiatkhachorn, E. Crouch, N. DeSilva, and T. Korfhagen Surfactant Protein-D Enhances Phagocytosis and Pulmonary Clearance of Respiratory Syncytial Virus Am. J. Respir. Cell Mol. Biol., August 1, 2004; 31(2): 193 - 199. [Abstract] [Full Text] [PDF]
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 M. J. Allen, A. Laederach, P. J. Reilly, R. J. Mason, and D. R. Voelker Arg343 in human surfactant protein D governs discrimination between glucose and N-acetylglucosamine ligands Glycobiology, August 1, 2004; 14(8): 693 - 700. [Abstract] [Full Text] [PDF]
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R. E. Oberley, K. A. Ault, T. L. Neff, K. R. Khubchandani, E. C. Crouch, and J. M. Snyder Surfactant proteins A and D enhance the phagocytosis of Chlamydia into THP-1 cells Am J Physiol Lung Cell Mol Physiol, August 1, 2004; 287(2): L296 - L306. [Abstract] [Full Text] [PDF]
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J. F. Alcorn and J. R. Wright Degradation of Pulmonary Surfactant Protein D by Pseudomonas aeruginosa Elastase Abrogates Innate Immune Function J. Biol. Chem., July 16, 2004; 279(29): 30871 - 30879. [Abstract] [Full Text] [PDF]
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K. Kudo, H. Sano#, H. Takahashi, K. Kuronuma, S.-i. Yokota, N. Fujii, K.-i. Shimada, I. Yano, Y. Kumazawa, D. R. Voelker, et al. Pulmonary Collectins Enhance Phagocytosis of Mycobacterium avium through Increased Activity of Mannose Receptor J. Immunol., June 15, 2004; 172(12): 7592 - 7602. [Abstract] [Full Text] [PDF]
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J. W. Lee, B. Ovadia, A. Azakie, S. Salas, J. Goerke, J. R. Fineman, and J. A. Gutierrez Increased pulmonary blood flow does not alter surfactant protein gene expression in lambs within the first week of life Am J Physiol Lung Cell Mol Physiol, June 1, 2004; 286(6): L1237 - L1243. [Abstract] [Full Text] [PDF]
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E. N. Atochina, M. F. Beers, S. Hawgood, F. Poulain, C. Davis, T. Fusaro, and A. J. Gow Surfactant Protein-D, a Mediator of Innate Lung Immunity, Alters the Products of Nitric Oxide Metabolism Am. J. Respir. Cell Mol. Biol., March 1, 2004; 30(3): 271 - 279. [Abstract] [Full Text] [PDF]
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J. M. Hickman-Davis, J. Gibbs-Erwin, J. R. Lindsey, and S. Matalon Role of Surfactant Protein-A in Nitric Oxide Production and Mycoplasma Killing in Congenic C57BL/6 Mice Am. J. Respir. Cell Mol. Biol., March 1, 2004; 30(3): 319 - 325. [Abstract] [Full Text] [PDF]
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 R. Leth-Larsen, C. Floridon, O. Nielsen, and U. Holmskov Surfactant protein D in the female genital tract Mol. Hum. Reprod., March 1, 2004; 10(3): 149 - 154. [Abstract] [Full Text] [PDF]
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R. Jounblat, A. Kadioglu, F. Iannelli, G. Pozzi, P. Eggleton, and P. W. Andrew Binding and Agglutination of Streptococcus pneumoniae by Human Surfactant Protein D (SP-D) Vary between Strains, but SP-D Fails To Enhance Killing by Neutrophils Infect. Immun., February 1, 2004; 72(2): 709 - 716. [Abstract] [Full Text] [PDF]
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J. F. Alcorn and J. R. Wright Surfactant protein A inhibits alveolar macrophage cytokine production by CD14-independent pathway Am J Physiol Lung Cell Mol Physiol, January 1, 2004; 286(1): L129 - L136. [Abstract] [Full Text] [PDF]
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 H Clark and K Reid The potential of recombinant surfactant protein D therapy to reduce inflammation in neonatal chronic lung disease, cystic fibrosis, and emphysema Arch. Dis. Child., November 1, 2003; 88(11): 981 - 984. [Abstract] [Full Text] [PDF]
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T. L. Noah, P. C. Murphy, J. J. Alink, M. W. Leigh, W. M. Hull, M. T. Stahlman, and J. A. Whitsett Bronchoalveolar Lavage Fluid Surfactant Protein-A and Surfactant Protein-D Are Inversely Related to Inflammation in Early Cystic Fibrosis Am. J. Respir. Crit. Care Med., September 15, 2003; 168(6): 685 - 691. [Abstract] [Full Text] [PDF]
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S.-Z. Wang, C. L. Rosenberger, Y.-X. Bao, J. M. Stark, and K. S. Harrod Clara Cell Secretory Protein Modulates Lung Inflammatory and Immune Responses to Respiratory Syncytial Virus Infection J. Immunol., July 15, 2003; 171(2): 1051 - 1060. [Abstract] [Full Text] [PDF]
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S.-J. Yong, Z. Vuk-Pavlovic, J. E. Standing, E. C. Crouch, and A. H. Limper Surfactant Protein D-Mediated Aggregation of Pneumocystis carinii Impairs Phagocytosis by Alveolar Macrophages Infect. Immun., April 1, 2003; 71(4): 1662 - 1671. [Abstract] [Full Text]
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S. Hussain, J. R. Wright, and W. J. Martin II Surfactant Protein A Decreases Nitric Oxide Production by Macrophages in a Tumor Necrosis Factor-{alpha}-Dependent Mechanism Am. J. Respir. Cell Mol. Biol., April 1, 2003; 28(4): 520 - 527. [Abstract] [Full Text] [PDF]
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T. L. Schagat, J. A. Wofford, K. E. Greene, and J. R. Wright Surfactant protein A differentially regulates peripheral and inflammatory neutrophil chemotaxis Am J Physiol Lung Cell Mol Physiol, January 1, 2003; 284(1): L140 - L147. [Abstract] [Full Text] [PDF]
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K. G. Brinker, H. Garner, and J. R. Wright Surfactant protein A modulates the differentiation of murine bone marrow-derived dendritic cells Am J Physiol Lung Cell Mol Physiol, January 1, 2003; 284(1): L232 - L241. [Abstract] [Full Text] [PDF]
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S. Hansen, D. Holm, V. Moeller, L. Vitved, C. Bendixen, K. B. M. Reid, K. Skjoedt, and U. Holmskov CL-46, a Novel Collectin Highly Expressed in Bovine Thymus and Liver J. Immunol., November 15, 2002; 169(10): 5726 - 5734. [Abstract] [Full Text] [PDF]
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K. L. Hartshorn, M. R. White, and E. C. Crouch Contributions of the N- and C-Terminal Domains of Surfactant Protein D to the Binding, Aggregation, and Phagocytic Uptake of Bacteria Infect. Immun., November 1, 2002; 70(11): 6129 - 6139. [Abstract] [Full Text] [PDF]
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W. T. Watford, M. B. Smithers, M. M. Frank, and J. R. Wright Surfactant protein A enhances the phagocytosis of C1q-coated particles by alveolar macrophages Am J Physiol Lung Cell Mol Physiol, November 1, 2002; 283(5): L1011 - L1022. [Abstract] [Full Text] [PDF]
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A. A. Beharka, C. D. Gaynor, B. K. Kang, D. R. Voelker, F. X. McCormack, and L. S. Schlesinger Pulmonary Surfactant Protein A Up-Regulates Activity of the Mannose Receptor, a Pattern Recognition Receptor Expressed on Human Macrophages J. Immunol., October 1, 2002; 169(7): 3565 - 3573. [Abstract] [Full Text] [PDF]
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N. Palaniyar, L. Zhang, A. Kuzmenko, M. Ikegami, S. Wan, H. Wu, T. R. Korfhagen, J. A. Whitsett, and F. X. McCormack The Role of Pulmonary Collectin N-terminal Domains in Surfactant Structure, Function, and Homeostasis in Vivo J. Biol. Chem., July 19, 2002; 277(30): 26971 - 26979. [Abstract] [Full Text] [PDF]
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 J. Akiyama, A. Hoffman, C. Brown, L. Allen, J. Edmondson, F. Poulain, and S. Hawgood Tissue Distribution of Surfactant Proteins A and D in the Mouse J. Histochem. Cytochem., July 1, 2002; 50(7): 993 - 996. [Abstract] [Full Text] [PDF]
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O. A. Quintero, T. R. Korfhagen, and J. R. Wright Surfactant protein A regulates surfactant phospholipid clearance after LPS-induced injury in vivo Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L76 - L85. [Abstract] [Full Text] [PDF]
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L. Zhang, K. L. Hartshorn, E. C. Crouch, M. Ikegami, and J. A. Whitsett Complementation of Pulmonary Abnormalities in SP-D(-/-) Mice with an SP-D/Conglutinin Fusion Protein J. Biol. Chem., June 14, 2002; 277(25): 22453 - 22459. [Abstract] [Full Text] [PDF]
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Y. He and E. Crouch Surfactant Protein D Gene Regulation. INTERACTIONS AMONG THE CONSERVED CCAAT/ENHANCER-BINDING PROTEIN ELEMENTS J. Biol. Chem., May 24, 2002; 277(22): 19530 - 19537. [Abstract] [Full Text] [PDF]
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V. L. Shepherd Distinct Roles for Lung Collectins in Pulmonary Host Defense Am. J. Respir. Cell Mol. Biol., March 1, 2002; 26(3): 257 - 260. [Full Text] [PDF]
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V. L. Shepherd Pulmonary surfactant protein D: a novel link between innate and adaptive immunity Am J Physiol Lung Cell Mol Physiol, March 1, 2002; 282(3): L516 - L517. [Full Text] [PDF]
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S. Murakami, D. Iwaki, H. Mitsuzawa, H. Sano, H. Takahashi, D. R. Voelker, T. Akino, and Y. Kuroki Surfactant Protein A Inhibits Peptidoglycan-induced Tumor Necrosis Factor-alpha Secretion in U937 Cells and Alveolar Macrophages by Direct Interaction with Toll-like Receptor 2 J. Biol. Chem., February 22, 2002; 277(9): 6830 - 6837. [Abstract] [Full Text] [PDF]
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J. S. Ferguson, D. R. Voelker, J. A. Ufnar, A. J. Dawson, and L. S. Schlesinger Surfactant Protein D Inhibition of Human Macrophage Uptake of Mycobacterium tuberculosis Is Independent of Bacterial Agglutination J. Immunol., February 1, 2002; 168(3): 1309 - 1314. [Abstract] [Full Text] [PDF]
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T. R. Korfhagen Surfactant Protein A (SP-A)-Mediated Bacterial Clearance . SP-A and Cystic Fibrosis Am. J. Respir. Cell Mol. Biol., December 1, 2001; 25(6): 668 - 672. [Full Text] [PDF]
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K. G. Brinker, E. Martin, P. Borron, E. Mostaghel, C. Doyle, C. V. Harding, and J. R. Wright Surfactant protein D enhances bacterial antigen presentation by bone marrow-derived dendritic cells Am J Physiol Lung Cell Mol Physiol, December 1, 2001; 281(6): L1453 - L1463. [Abstract] [Full Text] [PDF]
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W. T. Watford, J. R. Wright, C. G. Hester, H. Jiang, and M. M. Frank Surfactant Protein A Regulates Complement Activation J. Immunol., December 1, 2001; 167(11): 6593 - 6600. [Abstract] [Full Text] [PDF]
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A. M. LeVine, J. A. Whitsett, K. L. Hartshorn, E. C. Crouch, and T. R. Korfhagen Surfactant Protein D Enhances Clearance of Influenza A Virus from the Lung In Vivo J. Immunol., November 15, 2001; 167(10): 5868 - 5873. [Abstract] [Full Text] [PDF]
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J. M. Hickman-Davis, F. C. Fang, C. Nathan, V. L. Shepherd, D. R. Voelker, and J. R. Wright Lung surfactant and reactive oxygen-nitrogen species: antimicrobial activity and host-pathogen interactions Am J Physiol Lung Cell Mol Physiol, September 1, 2001; 281(3): L517 - L523. [Abstract] [Full Text] [PDF]
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M. Yoshida, T. R. Korfhagen, and J. A. Whitsett Surfactant Protein D Regulates NF-{{kappa}}B and Matrix Metalloproteinase Production in Alveolar Macrophages via Oxidant-Sensitive Pathways J. Immunol., June 15, 2001; 166(12): 7514 - 7519. [Abstract] [Full Text] [PDF]
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J. R. Wright, P. Borron, K. G. Brinker, and R. J. Folz Surfactant Protein A . Regulation of Innate and Adaptive Immune Responses in Lung Inflammation Am. J. Respir. Cell Mol. Biol., May 1, 2001; 24(5): 513 - 517. [Full Text]
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B. C. Trask, M. J. Malone, E. H. Lum, H. G. Welgus, E. C. Crouch, and S. D. Shapiro Induction of Macrophage Matrix Metalloproteinase Biosynthesis by Surfactant Protein D J. Biol. Chem., October 5, 2001; 276(41): 37846 - 37852. [Abstract] [Full Text] [PDF]
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) had increased total cell counts in BAL
fluid 6 h after GBS (A) and 6 and 24 h after
H. influenzae (B) infection.
SP-D-/- mice (
) had increased total cell counts in BAL
fluid 6 h after GBS (A) and 24 h after
H. influenzae (B) infection compared with
wild-type mice (
). Data are mean ± SEM with
n = 8 mice per group; *, p <
0.05 compared with wild-type mice.
