On the significance of Surfactant Protein-A within the human lungs
© Goldmann et al; licensee BioMed Central Ltd. 2009
Received: 06 March 2009
Accepted: 12 March 2009
Published: 12 March 2009
Surfactant Protein-A (SP-A) is the most prominent among four proteins in the pulmonary surfactant-system. SP-A is expressed by alveolar epithelial cells type II as well as by a portion of non small cell lung carcinomas (NSCLC).
The expression of SP-A is complexly regulated on the transcriptional and the chromosomal level. SP-A is a major player in the pulmonary cytokine-network and moreover has been described to act in the pulmonary host defense.
By the use of cell culture or animal models the functional properties have been repeatedly shown in many aspects, often bearing surprising properties which strongly indicate the physiological importance of SP-A. To date SP-A is recognized as a molecule essential for pulmonary development, structure and function. An upcoming number of reports deals with the role of SP-A for pulmonary pathology. This article gives an overview about the state of knowledge on SP-A focused in applications for human pulmonary disorders and points out the importance for pathology-orientated research approaches using immunohistochemistry or in situ hybridization as promising methods to further elucidate the role of this molecule in adult lung diseases.
The role of the surfactant system for the development of the human lung is known to be essential. Since it is synthesized by humans starting in the 28th week of pregnancy and reaching functional levels in the 34th week, surfactant-substitution-therapy is a fundamental part of the treatment of premature babies suffering from Infant Respiratory Distress Syndrome (IRDS).
Pulmonary surfactant regulates dynamically the alveolar surface tension. The central role of the surfactant system for maintaining pulmonary function has been repeatedly shown by the use of cell culture or animal models .
Surfactant is a complex mixture of lipids, carbohydrates and four proteins (SP-A, SP-B, SP-C, SP-D). The initial descriptions of surfactant lead back to the 1950s, but little attention was given to the surfactant proteins until the 1980s . The genes coding for these proteins are located on different chromosomes. SP-B and SP-C are similarly structured hydrophobic proteins participating in the adsorption of phospholipids at the alveolar border, which leads to rapid reduction of the surface tension. The hydrophilic proteins SP-A and SP-D are members of the collectins with C-type lectin domains. SP-D together with SP-A play a role in the pulmonary defense against Gram-negative bacteria .
SP-A: biochemical properties and genetic organization
SP-A in pulmonary diseases
In recent years the role of defects in the expression of SP-A in context with different pulmonary diseases has become an issue of scientific investigations. Initially numerous studies have been performed to elucidate the role of surfactant substitution in pediatrics .
As one major function SP-A displays a protective role of the molecule in pulmonary host defense by interacting with various infectious agents such as bacteria, fungi and viruses. SP-A deficient knock-out mice – compared to wild type animals – are susceptible to infections with Pseudomonas aeruginosa  and the clearance of group B streptococcus is slower . In accordance the defense of SP-A deficient mice against Respiratory Syncytial Virus (RSV) has been shown to be reduced and may be restored by exogenous SP-A administration [15–17].
By mediating the attachment of Mycobacterium tuberculosis to alveolar macrophages and promoting the phagocytosis of these bacteria, SP-A is important in the pathogenesis of tuberculosis [18–21]. SP-A also functionally interacts with staphylococci [22, 23], Haemophilus influenza Type A [24, 25], Pneumocystis carinii [26, 27], Influenza A Virus (less efficient than SP-D) , Candida tropicalis  and Aspergillus fumigatus .
Therefore it is likely that defects in the expression of SP-A may be important in the course of non infectious pulmonary diseases of adult patients. In the case of idiopathic pulmonary fibrosis, for example, low levels of SP-A (measured by ELISA) have been reported in broncho alveolar lavages (BAL), but elevated levels were found in the sera [32–34]. Immunohistochemical examinations of the expression of SP-A in pulmonary fibrosis demonstrated evident defects by using specimens from different diseases displaying fibrotic changes in the lungs. In good agreement with the results in BAL reduced levels of SP-A have been observed in fibrotic lungs. This reduced SP-A-expression in fibrotic lungs may be caused by two reasons: a limited number of the SP-A producing type II pneumocytes and by a clearly reduced SP-A expression of the remaining cells .
Reduced levels of SP-A have been demonstrated also in other pulmonary diseases such as the Adult Respiratory Distress Syndrome (ARDS) and in pneumonia .
Keeping in mind that surfactant substitutes are widely available due to their application in pediatrics, a growing number of therapeutic possibilities may result from these findings.
Since SP-A represents a central molecule in pulmonary immunoregulation as well as in host-defense it is obvious that defects in the surfactant system may have functional influence in the course of these pulmonary disorders.
However, the choice of a suitable SP-A antibody is highly important since approaches using polyclonals display cross reactions with other tumors . This procedure has already become a part of pathological routine diagnosis, and – along with other markers such as the Thyroid-transcription-factor-1 (TTF-1) – the detection of SP-A (by PE-10) is a useful part of the immunohistochemical panel in pulmonary pathology.
Immunohistochemical detection of SP-A even might be utilized for forensic purposes helping to distinguish between fatal drowning and postmortem immersion .
Taken together, SP-A is a complexly regulated molecule with surprising properties and essential importance for pulmonary development, structure and function which is getting more and more into focus concerning various diseases of the adult lung. Thus, as an outlook, it will become an issue of pulmonary pathology which might provide promising perspectives for applications in research, diagnosis and therapy.
The authors thank J. Tiebach and M. Lammers for excellent technical assistance.
- Gibson AT: Surfactant and the neonatal lung. Br J Hosp Med. 1997, 58: 381-384.PubMed
- Kattwinkel J: 2Surfactant. Evolving issues. Clin Pedinatol. 1998, 25 (1): 17-32.
- Floros J, Karinch AM: Human SP-A: then and now. Am J Physiol. 1995, 268: L162-L165.PubMed
- Hoppe HJ, Reid KBM: Collectins – soluble proteins containing collagenous regions and lectin domains – and their roles in innate immunity. Prot Sci. 1994, 3: 1143-1158. 10.1002/pro.5560030801.View Article
- Betz C, Papadopoulos Th, Buchwald J, Dämmrich J, Müller-Hermelink HK: Surfactant protein gene expresssion in metastatic and micrometastatic pulmonary adenocarcinomas and other non-small cell lung carcinomas: detection by reverse transcriptase-polymerase chain reaction. Cancer Res. 1995, 55: 4283-4286.PubMed
- Dempo K, Satoh M, Tsuji S, Mori M, Kuroki Y, Akino T: Immunohistochemical studies on the expression of pulmonary surfactant apoproteins in human lung carcinomas using monoclonal antibodies. Pathol Res Pract. 1987, 182: 669-675.View ArticlePubMed
- White RT, Damm D, Miller J, Spratt K, Schilling J, Hawgood S, Benson B, Cordell B: Isolation and characterization of the human pulmonary surfactant apoprotein gene. Nature. 1985, 317: 361-363. 10.1038/317361a0.View ArticlePubMed
- Korfhagen TR, Glasser SW, Bruno MD, McMahan MJ, Whitsett JA: A portion of the human surfactant protein A (SP-A) gene locus consists of a pseudogene. Am J Respir Cell Mol Biol. 1991, 4: 463-469.View ArticlePubMed
- Hickling TP, Malhorta R, Sim RB: Human lung surfactant protein A exsits in several different oligomeric states: oligomer size distribution varies between patient groups. Molecular Medicine. 1998, 4: 266-275.PubMed CentralPubMed
- McCormick SM, Mendelson CR: Human SP-A1 and SP-A2 genes are differentially regulated during development and by cAMP and glucocorticoids. Am J Physiol. 1994, 266: L367-L374. (Lung Cell Mol Physiol 10)PubMed
- McCormick SM, Boggaram V, Mendelson CR: Characterization of mRNA transcripts and organization of human SP-A1 and SP-A2 genes. Am J Physiol. 1994, 266: L354-366. (Lung Cell Mol Physiol 10)PubMed
- Korfhagen TR, Glasser SW, Stripp BR: Regulation of gene expression in the lung. Curr Opin Pediatr. 1994, 6: 255-261. 10.1097/00008480-199406000-00005.View ArticlePubMed
- LeVine AM, Kurak KE, Bruno MD, Stark JM, Whitsett JA, Korfhagen TR: Surfactant protein-A-deficient mice are susceptible to Pseudomonas aeruginosa infection. Am J Respir Cell Mol Biol. 1998, 19: 700-708.View ArticlePubMed
- LeVine AM, Kurak KE, Wright JR, Watford WT, Bruno MD, Ross GF, Whitsett JA, Korfhagen TR: Surfactant protein-A binds group B streptococcus enhancing phagocytosis and clearance from lungs of surfactant protein-A-deficient mice. Am J Respir Cell Mol Biol. 1999, 20: 279-286.View ArticlePubMed
- Kerr MH, Paton JY: Surfactant protein levels in severe respiratory syncytial virus infection. Am J Respir Crit Care Med. 1999, 159: 1115-1118.View ArticlePubMed
- LeVine AM, Gwozdz J, Stark J, Bruno M, Whitsett J, Korfhagen T: Surfactant protein-A enhances respiratory syncytial virus clearance in vivo. J Clin Invest. 1999, 103: 1015-1021. 10.1172/JCI5849.PubMed CentralView ArticlePubMed
- Van Schaik SM, Vargas I, Welliver RC, Enhorning G: Surfactant dysfunction develops BAB/c mice infected with respiratory syncytial virus. Pediatr Res. 1997, 42: 169-173. 10.1203/00006450-199708000-00007.View ArticlePubMed
- Downing JF, Pasula R, Wright JR, Twigg HL, Martin WJ: Surfactant protein a promotes attachment of Mycobacterium tuberculosis to alveolar macrophages during infection with human immunodeficiency virus. Proc Natl Acad Sci USA. 1995, 92: 4848-4852. 10.1073/pnas.92.11.4848.PubMed CentralView ArticlePubMed
- Gaynor CD, McCormack FX, Voelker DR, McGowan SE, Schlesinger LS: Pulmonary surfactant protein A mediates enhanced phagocytosis of Mycobacterium tuberculosis by a direct interaction with human macrophages. J Immunol. 1995, 155: 5343-5351.PubMed
- Martin WJ, Downing JF, Williams MD, Pasula R, Twigg HL, Wright JR: Role of surfactant protein A in the pathogenesis of tuberculosis in subjects with human immunodeficiency virus infection. Proc Assoc Am Physicians. 1995, 107: 340-345.PubMed
- Pasula R, Downing JF, Wright JR, Kachel DL, Davis TE, Martin WJ: Surfactant protein A (SP-A) mediates attachment of Mycobacterium tuberculosis to murine alveolar macrophages. Am J Respir Cell Mol Biol. 1997, 17: 209-217.View ArticlePubMed
- Manz-Keinke H, Plattner H, Schlepper-Schafer J: Lung surfactant protein A (SP-A) enhances serum-independent phagocytosis of bacteria by alveolar macrophages. Eur J Cell Biol. 1992, 57: 95-100.PubMed
- Van Iwaarden F, Welmers B, Verhoef J, Haagsman HP, van Golde LM: Pulmonary surfactant protein A enhances the host-defense mechanism of rat alveolar macrophages. Am J Respir Cell Mol Biol. 1990, 2: 91-98.View ArticlePubMed
- McNeely TB, Coonrod JD: Aggregation and opsonization of type A but not type B Hemophilus influenzae by surfactant protein A. Am J Respir Cell Mol Biol. 1994, 11: 114-122.View ArticlePubMed
- Tino MJ, Wright JR: Surfactant protein A stimulates phagocytosis of specific pulmonary pathogens by alveolar macrophages. Am J Physiol. 1996, 270: L677-L688.PubMed
- Koziel H, Phelps DS, Fishman JA, Armstrong MY, Richards FF, Rose RM: Surfactant protein-A reduces binding and phagocytosis of pneumocystis carinii by human alveolar macrophages in vitro. Am J Respir Cell Mol Biol. 1998, 18: 834-843.View ArticlePubMed
- Zimmerman PE, Voelker DR, McCormack FX, Paulsrud JR, Martin WJ: 120-kD surface glycoprotein of Pneumocystis carinii is a ligand for surfactant protein A. J Clin Invest. 1992, 89: 143-9. 10.1172/JCI115554.PubMed CentralView ArticlePubMed
- Hartshorn KL, White MR, Shepherd V, Reid K, Jensenius JC, Crouch EC: Mechanisms of anti-influenza activity of surfactant proteins A and D: comparison with serum collectins. Am J Physiol. 1997, 273: L1156-1166.PubMed
- Pison U, Max M, Neuendank A, Weissbach S, Pietschmann S: Host defence capacities of pulmonary surfactant: evidence for 'non-surfactant' functions of the surfactant system. Eur J Clin Invest. 1994, 24: 586-99. 10.1111/j.1365-2362.1994.tb01110.x.View ArticlePubMed
- Madan T, Eggleton P, Kishore U, Strong P, Aggrawal SS: Binding of pulmonary surfactant proteins A and D to Aspergillus fumigatus conidia enhances phagocytosis and killing by human neutrophils and alveolar macrophages. Infect Immun. 1997, 65: 3171-3179.PubMed CentralPubMed
- Arias-Diaz J, Vara E, Garcia C, Gomez M, Balibrea JL: Tumor necrosis factor-alpha inhibits synthesis of surfactant by isolated human type II pneumocytes. Eur J Surg. 1993, 159: 541-549.PubMed
- Honda Y, Kuroki Y, Shijubo N, Fujishima T, Takahashi H, Hosoda K, Akino T, Abe S: Aberrant appearance of lung surfactant protein A in sera of patients with idiopathic pulmonary fibrosis and its clinical significance. Respiration. 1995, 62 (2): 64-69. 10.1159/000196393.View ArticlePubMed
- Kuroki Y, Tsutahara S, Shijubo N, Takahashi H, Shiratori M, Hattori A, Honda Y, Abe S, Akino T: Elevated levels of lung surfactant protein A in sera from patients with idiopathic pulmonary fibrosis and pulmonary alveolar proteinosis. Am Rev Respir Dis. 1993, 147: 723-729.View ArticlePubMed
- McCormack FX, King TE, Bucher BL, Nielsen L, Mason RJ: Surfactant protein A predicts survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1995, 152 (2): 751-759.View ArticlePubMed
- Deutschbein ME, Goldmann T, Galle J, Vollmer E: Patterns of Surfactant Aporotein-A (SP-A) Expression in Pulmonary Fibrosis. E J Pathol. 1999, 5: 99-101.
- Gunther A, Siebert C, Schmidt R, Ziegler S, Grimminger F, Yabut M, Temmesfeld B, Walmrath D, Morr H, Seeger W: Surfactant alterations in severe pneumonia, acute respiratory distress syndrome, and cardiogenic lung edema. Am J Respir Crit Care Med. 1996, 153: 176-184.View ArticlePubMed
- Hamm H, Luhrs J, Guzman y Rotaeche J, Costabel U, Fabel H, Bartsch W: Elevated surfactant protein A in bronchoalveolar lavage fluids from sarcoidosis and hypersensitivity pneumonitis patients. Chest. 1994, 106 (6): 1766-1770. 10.1378/chest.106.6.1766.View ArticlePubMed
- Kinder BW, Brown KK, McCormack FX, Ix JH, Kervitsky A, Schwarz MI, King TE: Serum Surfactant Protein-A Is a Strong Predictor of Early Mortality in Idiopathic Pulmonary Fibrosis. Chest. 2009,
- Shimura S, Masuda T, Takishima T, Shirato K: Surfactant Protein-A concentration in airway secretions for the detection of pulmonary oedema. Eur Respir J. 1996, 9: 2525-2530. 10.1183/09031936.96.09122525.View ArticlePubMed
- Papadopoulos T: Detection of surfactant protein gene expression by reverse transcriptase-polymerase chain reaction (RT-PCR) identifies metastases and occult tumor spread of pulmonary adenocarcinomas. Verh Dtsch Ges Pathol. 1996, 80: LVII-LXI.PubMed
- Sugiyama K, Kawai T, Nakanishi K, Suzuki M: Histochemical reactivities of lectins and surfactant apoprotein in pulmonary adenocarcinomas and their metastases. Mod Pathol. 1992, 5: 273-276.PubMed
- Nicholson AG, McCormick CJ, Shimosato Y, Butcher DN, Sheppard MN: The value of PE-10, a monoclonal antibody against pulmonary surfactant, in distinguishing primary and metastatic lung tumors. Histopathol. 1995, 25: 57-60. 10.1111/j.1365-2559.1995.tb00291.x.View Article
- Goldmann T, Vollmer E: Immunohistochemical detection of SP-A is of diagnostik support in a patient suffering froma metastatic adenocarcinoma of the lungs. E J Pathol. 1999, 5: 993-998.
- Bejarano PA, Baughman RP, Biddinger PW, Miller MA, Fenoglio-Preiser C, Al-Kafaji B, Di Lauro R, Whitsett JA: Surfactant Proteins and Thyroid Transcription Factor-1 in Pulmonary and Breast Carcinomas. Mod Pathol. 1996, 9: 445-452.PubMed
- Stemberga V, Stifter S, Cuculiæ D, Coklo M, Bosnar A: Immunohistochemical surfactant protein-A expression: Fatal drowning vs. postmortem immersion. Med Hypotheses. 2009, 72: 413-415. 10.1016/j.mehy.2008.11.024. Epub 2009View ArticlePubMed
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