Mol. Hum. Reprod. Advance Access originally published online on January 29, 2004
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Molecular Human Reproduction, Vol. 10, No. 3, pp. 149-154, 2004
© European Society of Human Reproduction and Embryology 2004
Surfactant protein D in the female genital tract
1Immunology and Microbiology, Institute of Medical Biology, University of Southern Denmark, Winsloewparken 21, DK-5000 Odense C, 2Department of Gynaecology and Obstetrics and 3Department of Pathology, Odense University Hospital, 5000 Odense C, Denmark
4 To whom correspondence should be addressed. e-mail: uholmskov{at}health.sdu.dk
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Surfactant protein D (SP-D) plays a role in innate immunity against various pathogens and in vivo studies have demonstrated that SP-D also has anti-inflammatory properties. SP-D was originally demonstrated in alveolar type II cells, but recent studies have shown extrapulmonary expression of SP-D indicating a systemic role for the protein. This study describes the presence of SP-D in the female genital tract, the placenta and in amniotic fluid using immunohistochemistry and enzyme-linked immunosorbent assay. SP-D was observed in cells lining surface epithelium and secretory glands in the vagina, cervix, uterus, fallopian tubes and ovaries. In the placenta, SP-D was seen in all villous and extravillous trophoblast subpopulations. Endometrial presence of SP-D in non-pregnant women varied according to stage of the menstrual cycle and was up-regulated towards the secretory phase. It is suggested that endometrial SP-D may prevent intrauterine infection at the time of implantation and during pregnancy.
Key words: Key words: female genital tract/immunohistochemistry/inflammation/placenta/surfactant protein D
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Introduction |
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Prevention of genital tract infections is important for successful human implantation and is dependent on the innate and adaptive immune systems. Surfactant SP-D is a member of the collagenous subfamily of C-type lectins (collectins), which is involved in the innate host defence system. SP-D recognizes non-self carbohydrates and lipid moieties on the surface of bacterial, fungal and viral pathogens and mediates their elimination (Crouch, 2000). Structurally, SP-D is assembled from trimeric subunits. Each subunit consists of an N-terminal cross-linking domain, a collagenous region, a coiled-coil linking domain and a C-terminal carbohydrate recognition domain (CRD) (Crouch, 2000; Hakansson and Reid, 2000). Multimerization of the trimeric subunits of SP-D to dodecamers (four subunits in a cruciform-like structure) or higher oligomers permits bridging interactions between the SP-D CRD and the pathogens. Efficient microbial agglutination and activation of phagocytic cells by SP-D eliminates the microorganisms (Crouch et al., 2000; Crouch and Wright, 2001). In vitro studies have shown that SP-D binds to a variety of bacteria including group B Streptococcus (LeVine et al., 2000), Escherichia coli (Kuan et al., 1992; Pikaar et al., 1995) and Staphylococcus aureus (Hartshorn et al., 1998), which are microorganisms normally present in the female genital tract (Larsen and Monif, 2001). A recombinant fragment of SP-D has been used for treatment of infections and allergies in mice models and is therefore considered for use as a therapeutic agent in the treatment of humans (Clark and Reid, 2002; Kishore et al., 2002; Strong et al., 2002; Singh et al., 2003).
The major sites of SP-D synthesis and secretion are alveolar type II cells and unciliated bronchial epithelial cells. Consequently, research on host defence functions of SP-D has been restricted to the lung. Mice lacking SP-D develop chronic pulmonary inflammation including increments in number of inflammatory cells, cytokines and oxygen radicals (LeVine et al., 2000; Wert et al., 2000b). Target deletion of murine SP-D has also demonstrated a role for SP-D in lipid homeostasis in the lung (Botas et al., 1998; Wert et al., 2000b). Extrapulmonary distribution of SP-D mRNA and protein have been shown in cells lining epithelial surfaces and glandular cells in direct or indirect continuity with mucosal surfaces (Fisher and Mason, 1995; Motwani et al., 1995; Chailley-Heu et al., 1997; Crouch, 2000; Madsen et al., 2000; Paananen et al., 2001; van Rozendaal et al., 2001; Murray et al., 2002; Akiyama et al., 2002; Lin and Floros, 2002; Stahlman et al., 2002).
A variety of microorganisms are habitually colonizing the female genital tract. In case of pregnancy, ascending spread may cause premature rupture of fetal membranes and delivery. Accordingly, SP-D and natural antibiotics like defensins and secreted leukocyte protease inhibitor (SLP1) may protect against intrauterine infections (King et al., 2002). The aim of the present study was to evaluate the cellular localization of SP-D in the female genital tract.
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Materials and methods |
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Antibodies directed against human SP-D
Antibodies were produced as described previously (Lausen et al., 1999; Madsen et al., 2000; Leth-Larsen et al., 2003). The polyclonal anti-SP-D antibody K477 was raised against human recombinant neck-CRD while monoclonal anti-SP-D antibody Hyb 246-4 was raised against native SP-D purified from human amniotic fluid. Those antibodies were used for quantification of SP-D in an established SP-D enzyme-linked immunosorbent assay (ELISA). A monoclonal anti-SP-D antibody Hyb 245-1 was raised against human recombinant neck-CRD and used for immunohistochemistry. The specificity of immunostaining was verified by replacing the primary antibody with an unrelated monoclonal antibody of the same subclass as the SP-D antibody, as well as other conventional staining controls.
Immunohistochemistry
Normal female tissue from 28 non-pregnant and 32 pregnant women (gestational age 6–40 weeks) was obtained from the Department of Pathology, Odense University Hospital (Odense, Denmark). Specimens from non-pregnant, pre-menopausal women included proliferative, secretory and menstrual phases, but the hormonal status of these patients, i.e. serum progesterone concentrations, was not analysed. Formalin-fixed, paraffin-embedded tissues were cut into 4 µm sections and mounted onto ChemMate capillary gap slides (Dako, Glostrup, Denmark), dried in a slide oven at 60°C for 1 h, deparaffinated with xylene, and rehydrated with ethanol to distilled water. Blocking of endogenous biotin was done using the Dako Biotin Blocking System (Dako). Heat-induced epitope retrieval was done with microwave heating twice at 650 W for 15 min in 10 mmol/l Tris with 0.5 mmol/l EGTA at pH 9.0. The primary antibody (Hyb 245–1) was diluted 1:400 in ChemMate diluent and incubated for 25 min at room temperature. Staining procedures were performed in an automated immunostainer (TechMate 1000; Dako) in accordance with the ChemMate protocol using the biotin–streptavidin detection system (ChemMate-HRP/DAB; Dako). Nuclear counterstaining in Mayer’s haematoxylin was done for 30 s.
Quantification of SP-D
SP-D was quantified in amniotic fluid by a five-layered ELISA, as previously described (Leth-Larsen et al., 2003). Microtitre plates were coated with F(ab')2 anti-human SP-D IgG (K477) at 1 µg/ml in 0.05 mol/l sodium carbonate buffer, pH 9.6. After overnight incubation at 4°C, the plates were washed and left with washing buffer (TBS, 0.05% Tween 20 containing 5 mmol/l CaCl2) for 15 min at room temperature as a blocking step. Calibrator, control samples, and samples diluted as appropriate were then added and incubated overnight at 4°C. This was followed by successive incubations with biotinylated monoclonal anti-human SP-D antibody (Hyb 246-4), horseradish peroxidase-conjugated streptavidin and o-phenylenediamine in citrate–phosphate buffer, pH 5, containing 0.014% H2O2. H2SO4 stopped the colour reaction. Plates were read at 492 nm in a multi-channel spectrophotometer.
Gel filtration chromatography
Gel filtration chromatography was performed on 200 µl samples of a pool of amniotic fluid collected from six individuals at 38–42 weeks of gestation. The samples were applied to an analytical Superose 6 column connected to an FPLC system (Amersham Biosciences, Germany) using TBS, pH 7.4, containing 10 mmol/l EDTA as elutant at a flow rate of 30 ml/h. SP-D was quantified in each fraction by ELISA.
Human samples
All samples were kept at –20°C until analysed. Human amniotic fluid was obtained from amniocentesis at 14–16 weeks of gestation (n = 61) and from Caesarean sections at 38–42 weeks of gestation (n = 26). Samples were made available from the Department of Obstetrics and Gynaecology, Odense University Hospital (Odense, Denmark). The fluid was centrifuged at 1500 g, 4°C for 30 min followed by filtration on glass fibre filter.
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Immunohistochemical analysis of SP-D
The cellular localization of SP-D in the non-pregnant uterus was confined to endothelium and epithelium. In the corpus uteri, the cytoplasm of surface endometrium was consistently SP-D positive whereas stromal cells were SP-D negative. Morphological changes in the endometrium during the menstrual cycle were associated with a shift in SP-D expression. Thus, epithelium of glands in the proliferative phase was SP-D negative (Figure 1a) while epithelium in secretory and menstrual phases was SP-D positive (Figure 1b). The endothelium of arteries and veins was SP-D positive throughout the menstrual cycle. In the placenta, the cytoplasm of villous and extravillous trophoblast subpopulations was SP-D positive. This was the case in early (Figure 1c) and late gestations (Figure 1d). Interstitial and vascular trophoblasts invading the maternal host tissue were also SP-D positive (Figure 1d, e). Decidual cells of the pregnant uterus and mesenchymal cells of the villous core were SP-D negative.
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In the uterine cervix, the epithelium of the cervix and cervical glands was SP-D positive. The strongest staining was seen in cells closest to the basal membrane. A more faint staining was seen associated with the plasma membrane in cells located closer to the lumen (Figure 2a). In contrast, the stratified squamous epithelium lining the vaginal portion of the cervix was only SP-D positive within the cytoplasm (Figure 2b). The ciliated epithelium in the fallopian tube was SP-D positive (Figure 2c) and the cuboidal epithelium covering the ovarian surface, endothelium of ovarian blood vessels and epitheloid theca interna cells were SP-D positive. Granulosa and stromal cells were SP-D negative (Figure 2d, e). Theca lutein and granulosa cells of the corpus luteum were SP-D positive (Figure 2d and f).
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SP-D ELISA
Figure 3 shows the elution pattern from gel filtration chromatography of a pool of amniotic fluid with each fraction quantified by the SP-D ELISA. The elution profile shows two oligomeric forms of native SP-D with the high molecular form eluting close to void volume. No or only very low amounts of SP-D were measured in urine, seminal fluid and breast milk (data not shown).
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SP-D in amniotic fluid
SP-D in amniotic fluid was significantly increased during pregnancy. The average value of 0.11 µg/ml (95% CI: 0.09–0.13 µg/ml) at week 14–16 of gestation rose to 26.3 µg/ml (95% CI: 19.1–35.6 µg/ml) at term (38–42 weeks of pregnancy) (Figure 4).
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Discussion |
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This study evaluates the localization of SP-D in the placenta and in the female genital tract of non-pregnant women. The results presented substantiate the presence of extrapulmonary SP-D synthesis. SP-D was localized in cells lining epithelial surfaces and secretory glands, in endothelium of arteries and veins as previously observed (G.Sorensen et al., unpublished data), and in villous and extravillous trophoblasts of the placenta. SP-D was also found in hormone-producing cells of the ovary.
Preterm delivery is a major cause of perinatal mortality and morbidity before week 32 of gestation. Preterm rupture of membranes, delivery, low birthweight and perinatal infections are invariably associated with bacterial colonization of the vagina and cervix (Gibbs et al., 1992). The mucosal surfaces are the entrance for most pathogens. The vagina harbours a complex microflora, but only a small number of microorganisms will result in severe diseases (Cohen et al., 1984). Some infectious diseases causing acute inflammation in the female genital tract are sexually transmitted while others are idiopathic, caused by commensals that multiply rapidly.
The local defence mechanisms protecting the genitourinary tract are poorly understood, but the expression of SP-D at these sites makes it a candidate molecule to prevent uterine infection by limiting ascending infections.
It is interesting to note that the serum SP-D levels are genetically determined with a heritability factor h2 of 0.91 (Husby et al., 2002). Three biallelic gene polymorphisms have been genotyped for the coding sequence of human SP-D: codons corresponding to amino acid residues 11, 160 and 270 (Crouch et al., 1993; DiAngelo et al., 1999; Lahti et al., 2002). Two recent clinical studies have associated the SP-D variants of amino acid 11 with severe respiratory syncytial virus infection and susceptibility to tuberculosis (Floros et al., 2000; Lahti et al., 2002). It is therefore possible that the different allelic variants of SP-D may influence the susceptibility to intrauterine infection. Low levels of the serum collectin mannan-binding lectin has previously been linked to habitual abortion (Christiansen et al., 1999; Kilpatrick et al., 1995, 1999; Kruse et al., 2002).
SP-D mRNA and protein is also highly expressed in the uterus of mice (Akiyama et al., 2002). However, mice lacking SP-D (Spd–/–) survive and breed normally and have litters of the same size as their wild-type littermates. In mice, SP-D is therefore not an essential factor for breeding. However, the Spd–/– mice had an increased pulmonary lipid pool, and the mice spontaneously developed chronic pulmonary inflammation, increase in matrix metalloproteinase activity and oxidant production (Botas et al., 1998; Korfhagen et al., 1998; Wert et al., 2000a). Following bacterial infection, markers of inflammation such as increased leukocyte recruitment and production of proinflammatory cytokines were increased compared to wild-type mice (LeVine et al., 2000). The lack of SP-D was not reported to change the morphology of murine uterus and it is not known how the Spd–/– mice would react upon intrauterine infections.
The synthesis of SP-D is known to be developmentally and hormonally regulated and in fetal lung, the expression increased from the 21st week of gestation (Deterding et al., 1994; Mariencheck and Crouch, 1994; Dulkerian et al., 1996; Rust et al., 1996; Mori et al., 2002). Here we show that SP-D levels were increased 
240-fold in amniotic fluid from 0.11 µg/ml in week 14–16 of gestation to 26.3 µg/ml at term, supporting previous results showing that SP-D in amniotic fluid accelerates late in gestation (Crouch et al., 1991; Miyamura et al., 1994). Localization of SP-D in first and third trimester trophoblasts was apparently similar without up-regulation. The total number of syncytiotrophoblasts was, however, increasing towards term. Accordingly, amniotic fluid SP-D may originate from the fetal lung as well as from trophoblastic sources. No significant difference in serum SP-D levels of early (n = 20) and late term (n = 78) pregnant individuals was measured (unpublished results).
A major difference in the appearance of SP-D was observed in the epithelium of the endometrial glands during the menstrual cycle. SP-D was located in the endometrium during the secretory phase, but absent during the proliferative phase. In contrast, SP-D was observed at the surface epithelium of the endometrium and in the endothelium of uterine vessels independently of the cyclic phase. Accordingly, SP-D synthesis in glandular epithelial cells may be influenced and/or regulated by sex steroid hormones. There are few data on the regulation of SP-D expression. Glucocorticoids have been shown to increase the accumulation of SP-D mRNA in fetal rat lung as well as in human lung explants (Ogasawara et al., 1992; Deterding et al., 1994; Mariencheck and Crouch, 1994; Dulkerian et al., 1996). We have recently demonstrated that treatment with growth hormone increases SP-D serum concentrations significantly in adults with Turner syndrome (C.Gravholt et al., unpublished data). No full glucocorticoid response elements or other steroid hormone receptor binding sites are identified in the SP-D promotor, but the existence of specific cis-acting elements and transregulatory proteins of the CCAAT/enhancer-binding protein (C/EBP) family may also contribute to the regulation of the SP-D gene (He et al., 2000). To date, C/EBP are implicated in transcriptional responses to cAMP, glucocorticoids, thyroid hormone and insulin (Roesler, 2001). Consequently, it is possible that these factors respond to progesterone as well, but the regulation of SP-D in endocrine tissues needs further investigation.
In conclusion, the present study shows that SP-D is present throughout the female genital tract and that there is an endometrial cyclic variation in the expression of SP-D. We suggest that SP-D may take part in the innate immune system, preventing uterine infection by the mediation of elimination of pathogenic microorganisms. We only examined tissue from normal, healthy patients and it therefore remains to be elucidated whether the expression of SP-D will be altered in cases with infections and/or preterm delivery. Future studies may also elucidate whether SP-D genotypes can predict this.
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Acknowledgements |
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We acknowledge Professor Jes Westergaard for the contribution of amniotic fluid. This work was supported by The Danish Medical Research Council (No. 9902278), The Novo Nordic Foundation, The Fifth (EC) Framework Programme (contract No. QLK2000-00325) and ‘Fonden til Lægevidenskabens Fremme’.
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Submitted on November 4, 2003; accepted on November 10, 2003.
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 J. Meschi, E. C. Crouch, P. Skolnik, K. Yahya, U. Holmskov, R. Leth-Larsen, I. Tornoe, T. Tecle, M. R. White, and K. L. Hartshorn Surfactant protein D binds to human immunodeficiency virus (HIV) envelope protein gp120 and inhibits HIV replication J. Gen. Virol., November 1, 2005; 86(11): 3097 - 3107. [Abstract] [Full Text] [PDF]
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 R. Chaby, I. Garcia-Verdugo, Q. Espinassous, and L. A. Augusto Interactions between LPS and lung surfactant proteins Innate Immunity, June 1, 2005; 11(3): 181 - 185. [Abstract] [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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R. E. Oberley, K. L. Goss, K. A. Ault, E. C. Crouch, and J. M. Snyder Surfactant protein D is present in the human female reproductive tract and inhibits Chlamydia trachomatis infection Mol. Hum. Reprod., December 1, 2004; 10(12): 861 - 870. [Abstract] [Full Text] [PDF]
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