Surfactant protein A (SP-A)and SP-D are members of a family of immune proteins known as collectins, or collagen-like lectins.
SP-A and SP-D interact with various pathogens through their lectin domains and enhance pathogen uptake by phagocytes.
SP-A and SP-D regulate functions of a variety of immune cells, including dendritic cells, T cells, neutrophils and macrophages.
SP-A- and SP-D-null mice have an increased susceptibility to infection and inflammation.
Recent studies indicate that SP-A and SP-D might function at sites in addition to the lung, where they were first discovered and are most abundant.
SP-A has been shown to initiate an inflammatory response in the uterus and to induce labour.
Because the lungs function as the body's gas-exchange organ, they are inevitably exposed to air that is contaminated with pathogens, allergens and pollutants. Host-defence mechanisms within the lungs must facilitate clearance of inhaled pathogens and particles while minimizing an inflammatory response that could damage the thin, delicate gas-exchanging epithelium. Pulmonary surfactant is a complex of lipids and proteins that enhances pathogen clearance and regulates adaptive and innate immune-cell functions. In this article, I review the structure and functions of the surfactant proteins SP-A and SP-D in regulating host immune defence and in modulating inflammatory responses.
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Pattle, R. E. Properties, function and origin of the lining layer. Nature 175, 1125–1126 (1955).
Clements, J. A. Surface tension of lung extracts. Proc. Soc. Exp. Biol. Med. 95, 170–172 (1957).
Nogee, L. M. Alterations in SP-B and SP-C expression in neonatal lung disease. Annu. Rev. Physiol. 66, 601–623 (2004).
Augusto, L. A. et al. Interaction of pulmonary surfactant protein C with CD14 and lipopolysaccharide. Infect. Immun. 71, 61–67 (2003).
Augusto, L. A., Li, J., Synguelakis, M., Johansson, J. & Chaby, R. Structural basis for interactions between lung surfactant protein C and bacterial lipopolysaccharide. J. Biol. Chem. 277, 23484–23492 (2002).
Shulenin, S. et al. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N. Engl. J. Med. 350, 1296–1303 (2004).
Wirtz, H. R. W. & Dobbs, L. G. Calcium mobilization and exocytosis after one mechanical stretch of lung epithelial cells. Science 250, 1266–1269 (1990).
Haller, T. et al. Fusion pore expansion is a slow, discontinuous, and Ca2+-dependent process regulating secretion from alveolar type II cells. J. Cell Biol. 155, 279–289 (2001).
Walker, S. R., Williams, M. C. & Benson, B. Immunocytochemical localization of the major surfactant apoproteins in type II cells, Clara cells, and alveolar macrophages of rat lungs. J. Histochem. Cytochem. 34, 1137–1148 (1986).
Wong, C. J., Akiyama, J., Allen, L. & Hawgood, S. Localization and developmental expression of surfactant proteins D and A in the respiratory tract of the mouse. Pediatr. Res. 39, 930–937 (1996).
Rubio, S. et al. Pulmonary surfactant protein A (SP-A) is expressed by epithelial cells of small and large intestine. J. Biol. Chem. 270, 12162–12169 (1995).
Lin, Z. et al. Both human SP-A1 and SP–A2 genes are expressed in small and large intestine. Am. J. Respir. Crit. Care Med. 161, A43 (2000).
Madsen, J. et al. Localization of lung surfactant protein D on mucosal surfaces in human tissue. J. Immunol. 164, 5866–5870 (2000).
Leth-Larsen, R., Floridon, C., Nielsen, O. & Holmskov, U. Surfactant protein D in the female genital tract. Mol. Hum. Reprod. 10, 149–154 (2004).
Hansen, S. & Holmskov, U. Lung surfactant protein D (SP-D) and the molecular diverted descendants: conglutinin, CL-43 and CL-46. Immunobiology 205, 498–517 (2002).
Ohtani, K. et al. Molecular cloning of a novel human collectin from liver (CL-L1). J. Biol. Chem. 274, 13681–13689 (1999).
Ohtani, K. et al. The membrane-type collectin CL-P1 is a scavenger receptor on vascular endothelial cells. J. Biol. Chem. 276, 44222–44228 (2001).
Holmskov, U., Thiel, S. & Jensenius, J. C. Collectins and ficolins: humoral lectins of the innate immune defense. Annu. Rev. Immunol. 21, 547–578 (2003).
Bruns, G., Stroh, H., Veldman, G. M., Latt, S. A. & Floros, J. The 35 kD pulmonary surfactant-associated protein is encoded on chromosome 10. Hum. Genet. 76, 58–62 (1987).
Fisher, J. H. et al. The coding sequence for the 32,000-dalton pulmonary surfactant-associated protein A is located on chromosome 10 and identifies two separate restriction-fragment-length polymorphisms. Am. J. Hum. Genet. 40, 503–511 (1987).
Crouch, E., Rust, K., Veile, R., Donis-Keller, H. & Grosso, L. Genomic organization of human surfactant protein D (SP-D). J. Biol. Chem. 268, 2976–2983 (1993).
Drickamer, K. Two distinct classes of carbohydrate-recognition domains in animal lectins. J. Biol. Chem. 263, 9557–9560 (1988).
Haagsman, H. P. et al. The major lung surfactant protein, SP 28–36, is a calcium-dependent, carbohydrate-binding protein. J. Biol. Chem. 262, 13877–13880 (1987). This paper was the first to report that SP-A is a member of the collectin family of collagenous C-type lectins.
Persson, A., Chang, D. & Crouch, E. Surfactant protein D is a divalent cation-dependent carbohydrate-binding protein. J. Biol. Chem. 265, 5755–5760 (1990).
Lim, B. L., Wang, J. Y., Holmskov, U., Hoppe, H. J. & Reid, K. B. Expression of the carbohydrate recognition domain of lung surfactant protein D and demonstration of its binding to lipopolysaccharides of Gram-negative bacteria. Biochem. Biophys. Res. Commun. 202, 1674–1680 (1994).
Bordet, J. & Streng, O. Les phenomenes d'absorption de la conglutinin du serum de boeuf. Ann. Inst. Pasteur 49, 260–276 (1906) (in French).
Crouch, E. & Wright, J. R. Surfactant proteins A and D and pulmonary host defense. Annu. Rev. Physiol. 63, 521–554 (2001).
Shepherd, V. L. Distinct roles for lung collectins in pulmonary host defense. Am. J. Respir. Cell Mol. Biol. 26, 257–260 (2002). This succinct review contains tables listing the multiple pathogens that are bound by SP-A and SP-D and summarizing the responses of SP-A- and SP-D-null mice to a variety of pathogens.
McNeely, T. B. & Coonrod, J. D. Aggregation and opsonization of type A but not type B Hemophilus influenzae by surfactant protein A. Am. J. Respir. Cell Mol. Biol. 11, 114–122 (1994).
Chiba, H., Pattanajitvilai, S., Evans, A. J., Harbeck, R. J. & Voelker, D. R. Human surfactant protein D (SP-D) binds Mycoplasma pneumoniae by high affinity interactions with lipids. J. Biol. Chem. 277, 20379–20385 (2002).
Ferguson, J. S., Voelker, D. R., McCormack, F. X. & Schlesinger, L. S. Surfactant protein D binds to Mycobacterium tuberculosis bacilli and lipoarabinomannan via carbohydrate–lectin interactions resulting in reduced phagocytosis of the bacteria by macrophages. J. Immunol. 163, 312–321 (1999).
Hartshorn, K. L. et al. Mechanism of binding of surfactant protein D to influenza A viruses: importance of binding to haemagglutinin to antiviral activity. Biochem. J. 351, 449–458 (2000).
Reading, P. C., Morey, L. S., Crouch, E. C. & Anders, E. M. Collectin-mediated antiviral host defense of the lung: evidence from influenza virus infection of mice. J. Virol. 71, 8204–8212 (1997).
Hartshorn, K. et al. Mechanisms of anti-influenza activity of surfactant proteins A and D: comparison with serum collectins. Am. J. Physiol. Lung Cell. Mol. Physiol. 273, L1156–L1166 (1997).
Hickling, T. P. et al. A recombinant trimeric surfactant protein D carbohydrate recognition domain inhibits respiratory syncytial virus infection in vitro and in vivo. Eur. J. Immunol. 29, 3478–3484 (1999).
Ghildyal, R. et al. Surfactant protein A binds to the fusion glycoprotein of respiratory syncytial virus and neutralizes virion infectivity. J. Infect. Dis. 180, 2009–2013 (1999).
Tenner, A. J. Membrane receptors for soluble defense collagens. Curr. Opin. Immunol. 11, 34–41 (1999).
Malhotra, R., Lu, J., Holmskov, U. & Sim, R. B. Collectins, collectin receptors and the lectin pathway of complement activation. Clin. Exp. Immunol. 97, 4–9 (1994).
Nepomuceno, R. R., Henschen-Edman, A. H., Burgess, W. H. & Tenner, A. J. cDNA cloning and primary structure analysis of C1aRp, the human C1q/MBL/SPA receptor that mediates enhanced phagocytosis in vitro. Immunity 6, 119–129 (1997).
Steinberger, P. et al. Identification of human CD93 as the phagocytic C1q receptor (C1qRp) by expression cloning. J. Leukoc. Biol. 71, 133–140 (2002).
Malhotra, R., Willis, A., Jensenius, J., Jackson, J. & Sim, R. Structure and homology of human C1q receptor (collectin receptor). Immunology 78, 341–348 (1993).
Malhotra, R., Thiel, S., Reid, K. B. & Sim, R. B. Human leukocyte C1q receptor binds other soluble proteins with collagen domains. J. Exp. Med. 172, 955–959 (1990).
Gardai, S. J. et al. By binding SIRPα or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation. Cell 115, 13–23 (2003). This is a compelling study showing that SP-A and SP-D bind two distinct receptors: SIRP-α and CD91–calreticulin.
Gagnon, E. et al. Endoplasmic reticulum-mediated phagocytosis is a mechanism of entry into macrophages. Cell 110, 119–131 (2002).
Chroneos, Z. C., Abdolrasulnia, R., Whitsett, J. A., Rice, W. R. & Shepherd, V. L. Purification of a cell-surface receptor for surfactant protein A. J. Biol. Chem. 271, 16375–16383 (1996). This paper was the first to report the characterization of an SP-A receptor.
Borron, P. et al. Surfactant protein A inhibits T cell proliferation via its collagen-like tail and a 210-kDa receptor. Am. J. Physiol. Lung Cell. Mol. Physiol. 275, L679–L686 (1998).
Weikert, L. F. et al. SP-A enhances uptake of bacillus Calmette-Guerin by macrophages through a specific SP-A receptor. Am. J. Physiol. Lung Cell. Mol. Physiol. 272, L989–L995 (1997).
Weikert, L. F., Lopez, J. P., Abdolrasulnia, R., Chroneos, Z. C. & Shepherd, V. L. Surfactant protein A enhances mycobacterial killing by rat macrophages through a nitric oxide-dependent pathway. Am. J. Physiol. Lung Cell. Mol. Physiol. 279, L216–L223 (2000).
Holmskov, U. et al. Isolation and characterization of a new member of the scavenger receptor superfamily, glycoprotein-340 (gp-340), as a lung surfactant protein-D binding molecule. J. Biol. Chem. 272, 13743–13749 (1997).
Prakobphol, A. et al. Salivary agglutinin, which binds Streptococcus mutans and Helicobacter pylori, is the lung scavenger receptor cysteine-rich protein gp-340. J. Biol. Chem. 275, 39860–39866 (2000).
Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).
Guillot, L. et al. The immunostimulatory activity of the lung surfactant protein-A involves Toll-like receptor 4. J. Immunol. 168, 5989–5992 (2002).
Sato, M. et al. Direct binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-κB activation and TNF-α secretion are down-regulated by lung collectin surfactant protein A. J. Immunol. 171, 417–425 (2003).
van Iwaarden, F., Welmers, B., Verhoef, J., Haagsman, H. P. & van Golde, L. M. Pulmonary surfactant protein A enhances the host-defense mechanism of rat alveolar macrophages. Am. J. Respir. Cell Mol. Biol. 2, 91–98 (1990). This report was the first to show that SP-A enhances phagocytosis of bacteria.
Shepherd, V. L. Pulmonary surfactant protein D: a novel link between innate and adaptive immunity. Am. J. Physiol. Lung Cell. Mol. Physiol. 282, L516–L517 (2002).
Ferguson, J. S., Voelker, D. R., Ufnar, J. A., Dawson, A. J. & Schlesinger, L. S. Surfactant protein D inhibition of human macrophage uptake of Mycobacterium tuberculosis is independent of bacterial agglutination. J. Immunol. 168, 1309–1314 (2002).
Koziel, H. et al. Surfactant protein-A reduces binding and phagocytosis of Pneumocystis carinii by human alveolar macrophages in vitro. Am. J. Respir. Cell Mol. Biol. 18, 834–843 (1998).
Tenner, A. J., Robinson, S. L., Borchelt, J. & Wright, J. R. Human pulmonary surfactant protein (SP-A), a protein structurally homologous to C1q, can enhance FcR- and CR1-mediated phagocytosis. J. Biol. Chem. 264, 13923–13928 (1989). This study was the first to show that surfactant proteins enhance uptake of particles by immune cells.
Kuronuma, K. et al. Pulmonary surfactant protein A augments the phagocytosis of Streptococcus pneumoniae by alveolar macrophages through a casein kinase 2-dependent increase of cell surface localization of scavenger receptor A. J. Biol. Chem. 279, 21421–21430 (2004).
Pasula, R., Wright, J. R., Kachel, D. L. & Martin, W. M. Surfactant protein A suppresses reactive nitrogen intermediates by the alveolar macrophages in response to Mycobacterium tuberculosis. J. Clin. Invest. 103, 483–490 (1999).
Beharka, A. A. et al. Pulmonary surfactant protein A up-regulates activity of the mannose receptor, a pattern recognition receptor expressed on human macrophages. J. Immunol. 169, 3565–3573 (2002).
Rosseau, S. et al. Surfactant protein A down-regulates proinflammatory cytokine production evoked by Candida albicans in human alveolar macrophages and monocytes. J. Immunol. 163, 4495–4502 (1999).
McIntosh, J. C., Mervin-Blake, S., Conner, E. & Wright, J. R. Surfactant protein A protects growing cells and reduces TNF-α activity from LPS-stimulated macrophages. Am. J. Physiol. Lung Cell. Mol. Physiol. 271, L310–L319 (1996).
Hickling, T. P., Sim, R. B. & Malhotra, R. Induction of TNF-α release from human buffy coat cells by Pseudomonas aeruginosa is reduced by lung surfactant protein A. FEBS Lett. 437, 65–69 (1998).
Kremlev, S. G., Umstead, T. M. & Phelps, D. S. Surfactant protein A regulates cytokine production in the monocytic cell line THP-1. Am. J. Physiol. Lung Cell. Mol. Physiol. 272, L996–L1004 (1997).
Kremlev, S. G. & Phelps, D. S. Surfactant protein A stimulation of inflammatory cytokine and immunoglobulin production. Am. J. Physiol. Lung Cell. Mol. Physiol. 267, L712–L719 (1994).
Sano, H. et al. Pulmonary surfactant protein A modulates the cellular response to smooth and rough lipopolysaccharides by interaction with CD14. J. Immunol. 163, 387–395 (1999).
Stamme, C. & Wright, J. R. Surfactant protein A enhances interferon γ-induced nitric oxide but inhibits LPS-induced nitric oxide alveolar macrophages. Am. J. Respir. Crit. Care Med. 161, A515 (2000).
Hickman-Davis, J., Gibbs-Erwin, J., Lindsey, J. R. & Matalon, S. Surfactant protein A mediates mycoplasmacidal activity of alveolar macrophages by production of peroxynitrite. Proc. Natl Acad. Sci. USA 96, 4953–4958 (1999).
Crouch, E., Hartshorn, K. & Ofek, I. Collectins and pulmonary innate immunity. Immunol. Rev. 173, 52–65 (2000).
Hartshorn, K. L. et al. Human mannose-binding protein functions as an opsonin for influenza-A viruses. J. Clin. Invest. 91, 1414–1420 (1993).
Hartshorn, K., Chang, D., Rust, K. & Crouch, E. Interactions of recombinant human pulmonary surfactant protein D and SP-D multimers with influenza A. Am. J. Physiol. Lung Cell. Mol. Physiol. 271, L753–L762 (1996).
Benne, C. A. et al. Interactions of surfactant protein A with influenza A viruses: binding and neutralization. J. Infect. Dis. 171, 335–341 (1995).
Hartshorn, K. L. et al. Evidence for a protective role of pulmonary surfactant protein D (SP-D) against influenza A viruses. J. Clin. Invest. 94, 311–319 (1994).
Fadok, V. A. & Henson, P. M. Apoptosis: giving phosphatidylserine recognition an assist — with a twist. Curr. Biol. 13, R655–R657 (2003).
Burns, A. R., Smith, C. W. & Walker, D. C. Unique structural features that influence neutrophil emigration into the lung. Physiol. Rev. 83, 309–336 (2003).
Xing, Z. et al. Cytokine expression by neutrophils and macrophages in vivo: endotoxin induces tumor necrosis factor-α, macrophage inflammatory protein-2, interleukin-1β beta, and interleukin-6 but not RANTES or transforming growth factor-β1 mRNA expression in acute lung inflammation. Am. J. Respir. Cell Mol. Biol. 10, 148–153 (1994).
Akgul, C., Moulding, D. A. & Edwards, S. W. Molecular control of neutrophil apoptosis. FEBS Lett. 487, 318–322 (2001).
Schagat, T. L., Wofford, J. A. & Wright, J. R. Surfactant protein A enhances alveolar macrophage phagocytosis of apoptotic neutrophils. J. Immunol. 166, 2727–2733 (2001). The ability of SP-A to enhance phagocytosis of apoptotic cells was first reported in this publication.
Vandivier, R. W. et al. Role of surfactant proteins A, D, and C1q in the clearance of apoptotic cells in vivo and in vitro: calreticulin and CD91 as a common collectin receptor complex. J. Immunol. 169, 3978–3986 (2002).
Clark, H. et al. Surfactant protein D reduces alveolar macrophage apoptosis in vivo. J. Immunol. 169, 2892–2899 (2002).
Palaniyar, N. et al. Nucleic acid is a novel ligand for innate immune pattern recognition collectins surfactant proteins A and D and mannose-binding lectin. J. Biol. Chem. 279, 32728–32736 (2004).
Palaniyar, N., Clark, H., Nadesalingam, J., Hawgood, S. & Reid, K. B. Surfactant protein D binds genomic DNA and apoptotic cells, and enhances their clearance, in vivo. Ann. NY Acad. Sci. 1010, 471–475 (2003).
Palaniyar, N., Nadesalingam, J. & Reid, K. B. Innate immune collectins bind nucleic acids and enhance DNA clearance in vitro. Ann. NY Acad. Sci. 1010, 467–470 (2003).
Fadok, V. A. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2, and PAF. J. Clin. Invest. 101, 890–898 (1998).
Reidy, M. F. & Wright, J. R. Surfactant protein A enhances apoptotic cell uptake and TGF-β1 release by inflammatory alveolar macrophages. Am. J. Physiol. Lung Cell Mol. Physiol. 285, L854–L861 (2003).
Lipscomb, M. F. & Masten, B. J. Dendritic cells: immune regulators in health and disease. Physiol. Rev. 82, 97–130 (2002).
Havenith, C. E., Breedijk, A. J. & Hoefsmit, E. C. Effect of bacillus Calmette-Guerin inoculation on numbers of dendritic cells in bronchoalveolar lavages of rats. Immunobiology 184, 336–347 (1992).
Gong, J. L. Intraepithelial airway dendritic cells: a distinct subset of pulmonary dendritic cells obtained by microdissection. J. Exp. Med. 175, 797–807 (1992).
Sertl, K. et al. Dendritic cells with antigen-presenting capability reside in airway epithelium, lung, parenchyma, and visceral pleura. J. Exp. Med. 163, 436–451 (1986).
Holt, P. G., Schon-Hegrad, M. A. & Oliver, J. MHC class II antigen-bearing dendritic cells in pulmonary tissues of the rat. J. Exp. Med. 167, 262–274 (1988).
Lambrecht, B. N., Carro-Muino, I., Vermaelen, K. & Pauwels, R. A. Allergen-induced changes in bone-marrow progenitor and airway dendritic cells in sensitized rats. Am. J. Respir. Cell Mol. Biol. 20, 1165–1174 (1999).
Havenith, C. E., van Miert, P. P., Breedijk, A. J., Beelen, R. H. & Hoefsmit, E. C. Migration of dendritic cells into the draining lymph nodes of the lung after intratracheal instillation. Am. J. Respir. Cell Mol. Biol. 9, 484–488 (1993).
Havenith, C. E. et al. Separation of alveolar macrophages and dendritic cells via autofluorescence: phenotypical and functional characterization. J. Leukoc. Biol. 53, 504–510 (1993).
Brinker, K. G. et al. Surfactant protein D enhances bacterial antigen presentation by bone marrow-derived dendritic cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 281, L1453–L1463 (2001).
Brinker, K. G., Garner, H. & Wright, J. R. Surfactant protein A modulates the differentiation of murine bone marrow-derived dendritic cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 284, L232–L241 (2003).
Ansfield, M. J., Kaltreider, H. B., Caldwell, J. L. & Herskowitz, F. N. Hyporesponsiveness of canine bronchoalveolar lymphocytes to mitogens: inhibition of lymphocyte proliferation by alveolar macrophages. J. Immunol. 122, 542–548 (1979).
Ansfield, M. J., Kaltreider, H. B., Benson, B. J. & Caldwell, J. L. Immunosuppressive activity of canine pulmonary surface active material. J. Immunol. 122, 1062–1066 (1979).
Borron, P. et al. Surfactant associated protein-A inhibits human lymphocyte proliferation and IL-2 production. Am. J. Respir. Cell Mol. Biol. 15, 115–121 (1996).
Borron, P. J. et al. Recombinant rat surfactant-associated protein D inhibits human T lymphocyte proliferation and IL-2 production. J. Immunol. 161, 4599–4603 (1998).
Wang, J. Y., Shieh, C. C., You, P. F., Lei, H. Y. & Reid, K. B. Inhibitory effect of pulmonary surfactant proteins A and D on allergen-induced lymphocyte proliferation and histamine release in children with asthma. Am. J. Respir. Crit. Care Med. 158, 510–518 (1998).
Borron, P. J. et al. Pulmonary surfactant proteins A and D directly suppress CD3+/CD4+ cell function: evidence for two shared mechanisms. J. Immunol. 169, 5844–5850 (2002).
Fisher, J. H., Larson, J., Cool, C. & Dow, S. W. Lymphocyte activation in the lungs of SP-D null mice. Am. J. Respir. Cell Mol. Biol. 27, 24–33 (2002).
Wu, H. et al. Surfactant proteins A and D inhibit the growth of Gram-negative bacteria by increasing membrane permeability. J. Clin. Invest. 111, 1589–1602 (2003). The finding that SP-A and SP-D have direct antibacterial activity was reported in this paper.
Schaeffer, L. M., McCormack, F. X., Wu, H. & Weiss, A. A. Bordetella pertussis lipopolysaccharide resists the bactericidal effects of pulmonary surfactant protein A. J. Immunol. 173, 1959–1965 (2004).
McCormack, F. X. et al. Macrophage-independent fungicidal action of the pulmonary collectins. J. Biol. Chem. 278, 36250–36256 (2003).
van Rozendaal, B. A., van Spriel, A. B., van De Winkel, J. G. & Haagsman, H. P. Role of pulmonary surfactant protein D in innate defense against Candida albicans. J. Infect. Dis. 182, 917–922 (2000).
Condon, J. C., Jeyasuria, P., Faust, J. M. & Mendelson, C. R. Surfactant protein secreted by the maturing mouse fetal lung acts as a hormone that signals the initiation of parturition. Proc. Natl Acad. Sci. USA 101, 4978–4983 (2004). This surprising study provides evidence that SP-A induces inflammation in the uterus, which results in initiation of labour and delivery.
Romero, R. et al. Infection in the pathogenesis of preterm labor. Semin. Perinatol. 12, 262–279 (1988).
MacNeill, C. et al. Surfactant protein A, an innate immune factor, is expressed in the vaginal mucosa and is present in vaginal lavage fluid. Immunology 111, 91–99 (2004).
Korfhagen, T. R. et al. Altered surfactant function and structure in SP-A gene targeted mice. Proc. Natl Acad. Sci. USA 93, 9594–9599 (1996).
LeVine, A. M. et al. Surfactant protein-A deficient mice are susceptible to group B streptococcal infection. J. Immunol. 158, 4336–4340 (1997). The observation that SP-A-null mice have enhanced susceptibility to infection and inflammation was first reported in this paper. Subsequent studies extend this finding to show that SP-A-null mice have enhanced susceptibility to many different bacteria and viruses.
Korfhagen, T. R. et al. Surfactant protein D regulates surfactant phospholipid homeostasis in vivo. J. Biol. Chem. 273, 28438–28443 (1998).
Botas, C. et al. Altered surfactant homeostasis and alveolar type II cell morphology in mice lacking surfactant protein D. Proc. Natl Acad. Sci. USA 95, 11869–11874 (1998).
Wert, S. E. et al. Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice. Proc. Natl Acad. Sci. USA 97, 5972–5977 (2000).
Borron, P. et al. Surfactant-associated protein A inhibits LPS-induced cytokine and nitric oxide production in vivo. Am. J. Physiol. Lung Cell. Mol. Physiol. 278, L840–L847 (2000).
LeVine, A. M. et al. Distinct effects of surfactant protein A or D deficiency during bacterial infection on the lung. J. Immunol. 165, 3934–3940 (2000).
LeVine, A. M. et al. Surfactant protein-D enhances phagocytosis and pulmonary clearance of respiratory syncytial virus. Am. J. Respir. Cell Mol. Biol. 31, 193–199 (2004).
LeVine, A. M., Whitsett, J. A., Hartshorn, K. L., Crouch, E. C. & Korfhagen, T. R. Surfactant protein D enhances clearance of influenza A virus from the lung in vivo. J. Immunol. 167, 5868–5873 (2001).
Super, M., Thiel, S., Lu, J., Levinsky, R. J. & Turner, M. W. Association of low levels of mannan-binding protein with a common defect of opsonisation. Lancet 2, 1236–1239 (1989).
Lipscombe, R. J. et al. High frequencies in African and non-African populations of independent mutations in the mannose binding protein gene. Hum. Mol. Genet. 1, 709–715 (1992).
Jack, D. L., Klein, N. J. & Turner, M. W. Mannose-binding lectin: targeting the microbial world for complement attack and opsonophagocytosis. Immunol. Rev. 180, 86–99 (2001).
Floros, J. et al. Surfactant protein genetic marker alleles identify a subgroup of tuberculosis in a Mexican population. J. Infect. Dis. 182, 1473–1478 (2000).
Floros, J. et al. Family-based transmission disequilibrium test (TDT) and case-control association studies reveal surfactant protein A (SP-A) susceptibility alleles for respiratory distress syndrome (RDS) and possible race differences. Clin. Genet. 60, 178–187 (2001).
Guo, X. et al. Polymorphisms of surfactant protein gene A, B, D, and of SP-B-linked microsatellite markers in COPD of a Mexican population. Chest 117, 249S–250S (2000).
Lofgren, J., Ramet, M., Renko, M., Marttila, R. & Hallman, M. Association between surfactant protein A gene locus and severe respiratory syncytial virus infection in infants. J. Infect. Dis. 185, 283–289 (2002).
Lahti, M. et al. Surfactant protein D gene polymorphism associated with severe respiratory syncytial virus infection. Pediatr. Res. 51, 696–699 (2002).
Wang, G., Phelps, D. S., Umstead, T. M. & Floros, J. Human SP-A protein variants derived from one or both genes stimulate TNF-α production in the THP-1 cell line. Am. J. Physiol. Lung Cell. Mol. Physiol. 278, L946–L954 (2000).
Wang, G., Bates-Kenney, S. R., Tao, J. Q., Phelps, D. S. & Floros, J. Differences in biochemical properties and in biological function between human SP-A1 and SP-A2 variants, and the impact of ozone-induced oxidation. Biochemistry 43, 4227–4239 (2004).
Hermans, C. & Bernard, A. Lung epithelium-specific proteins. Am. J. Respir. Crit. Care Med. 159, 646–678 (1999).
Kuroki, Y., Takahashi, H., Chiba, H. & Akino, T. Surfactant proteins A and D: disease markers. Biochim. Biophys. Acta 1408, 334–345 (1998).
Jobe, A. H. Pulmonary surfactant therapy. N. Engl. J. Med. 328, 861–868 (1993).
Malloy, M. H. & Freeman, D. H. Respiratory distress syndrome mortality in the United States, 1987 to 1995. J. Perinatol. 20, 414–420 (2000).
Nogee, L. M. Genetic mechanisms of surfactant deficiency. Biol. Neonate 85, 314–318 (2004).
Crouch, E. C. Collectins and pulmonary host defense. Am. J. Respir. Cell Mol. Biol. 19, 177–201 (1998).
Wright, J. R. Immunomodulatory functions of surfactant. Physiol. Rev. 77, 931–962 (1997).
My sincere thanks to S. L. Young and to Wright Lab members, M. Bolger, K. Evans, S. Giles, R. Lovingood, D. Malherbe, J. Malloy and M. Reidy, for their critical review of the manuscript. I extend my sincere apologies to those colleagues whose original work could not be cited due to space limitations. My laboratory is supported by grants from the National Institutes of Health (United States).
The author declares no competing financial interests.
- RESPIRATORY-DISTRESS SYNDROME
A disease that affects premature newborns, resulting in increased difficulty in breathing. The disease is caused by a lack of surfactant, which helps to keep the lungs from collapsing.
- CHRONIC OBSTRUCTIVE PULMONARY DISEASE
(COPD). A group of lung diseases in which air-flow is limited and there is airway inflammation and destruction of lung tissue.
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