Pulmonary surfactant and its apoproteins. S Hawgood, J A Clements J Clin Invest. 1990;86(1):1-6. https://doi.org/10.1172/JCI114670. Research Article Find the latest version: https://jci.me/114670/pdf Perspectives Pulmonary Surfactant and Its Apoproteins Samuel Hawgood and John A. Clements Cardiovascular Research Institute and Department ofPediatrics, University of California San Francisco, San Francisco, California 94143-0130 Introduction This is the structure that lowers surface tension and helps sta- Six decades have gone by since Kurt von Neergaard published bilize the lung. The lining liquid also contains small vesicles his classical work on the effects of surface tension on the me- ( 12) whose function is not certain. Sequential centrifugation of chanical properties of the lungs (1). For three decades his in- surfactant obtained by lavage of the lung gives subfractions sights were largely ignored by medical scientists. Interest in his that are enriched in multilayer vesicles and tubular myelin or results became widespread after the discovery that the lung in small vesicles (9). Interestingly, the former material lowers regulates its surface tension by lining itself with surfactant (2, surface tension rapidly, is preferentially taken up from the 3), and that deficiency of this vital material is the proximate alveoli, and contains surfactant apoproteins, whereas the latter cause of respiratory distress syndrome in premature infants lacks apoproteins and functions poorly (9, 10). Experiments (4). In the last three decades investigators have brought to bear with radioactive labeling of surfactant components suggest a wide variety of research disciplines on the surfactant system that they cycle through these forms and are taken back into the of the lung and have generated a large fund of information type II cells, reassembled, and resecreted (9, 10, 13-15). Thus, about this complex system (5, 6). Currently, the most modern the apoproteins appear to determine important characteristics methods of biological research are being applied to lung sur- ofthe surfactant. The structure and properties ofthe surfactant factant with the result that our understanding of its functions, apoproteins are the focus of the remainder of this perspective. components, and metabolism is increasing with unprece- Apoprotein A dented speed. Concomitantly, practical application of these fundamental research results to common lung diseases has Surfactant protein A (SP-A)' is the most abundant and best begun in earnest, especially in newborn and adult respiratory characterized of the surfactant proteins. Approximately 3 mg distress syndromes where treatment with exogenous surfac- of SP-A is associated with each 100 mg of phospholipid in the tants is being evaluated (7). surfactant recovered from bronchoalveolar lavage. The pro- This reduction to practice does not mean, however, that tein, first identified in 1973 (16), is a large lung-specific glyco- the research on pulmonary surfactant is completed. Many protein synthesized in both the alveolar type II cell and the questions about its functions remain unanswered, particularly bronchiolar Clara cell (17, 18). Although SP-A can be isolated those mediated by its apoproteins, and these are the main from the surfactant lipids in vitro in a water-soluble form, no subject of this essay. But first, the complex nature of the sur- significant pool of SP-A free of lipid has been identified in factant deserves comment. vivo. The synthesis of SP-A is developmentally regulated. The Heterogeneity ofpulmonary surfactant protein is detectable in the lung only during the last third of It is well known that lung surfactant as commonly isolated human fetal gestation and is secreted into the alveolar space contains many kinds of molecules: phospholipids, cholesterol, and therefore detectable in amniotic fluid from - 34 wk ges- other neutral lipids, and many proteins (8). It is not so often tation (19). The concentration of SP-A correlates well with the pointed out that the surfactant is also morphologically and concentration of surfactant phospholipid in amniotic fluid functionally heterogeneous (9) (see Fig. 1) and that differences during gestation and inversely with the incidence of respira- in form and activity correlate with apoprotein content (9, 10). tory distress syndrome (19). The mechanisms involved in this When stored in the lamellar bodies of the alveolar type II cells, developmental regulation of SP-A gene expression are clearly the surfactant is tightly packed in multilayer arrays. Upon complex. Transcription of the SP-A gene in cultured lung secretion and hydration in the alveolar lining liquid, it expands preparations can be regulated by a number of hormones and into a complicated, latticelike structure called tubular myelin, growth factors including glucocorticoids, cAMP, insulin, in- from which the interfacial monolayer appears to spread (1 1). terferon gamma, epidermal growth factor, and transforming growth factor beta (20), but to date only glucocorticoids have been shown to effect the synthesis of SP-A in vivo (21). Address reprint requests to Samuel Hawgood, Box 0130, Cardiovascu- The human SP-A primary translation product is 248 lar Research Institute, University of California San Francisco, San Francisco, CA 94143. amino acids long with a molecular mass of 28,000 D (22, 23). Received for publication 2 February 1990 and in revised form 30 A number of modifications are made to the SP-A amino acid April 1990. chain during cellular processing. The amino-terminal one- third of the protein is rich in glycine and proline residues. J. Clin. Invest. © The American Society for Clinical Investigation, Inc. 0021-9738/90/07/0001/06 $2.00 1. Abbreviations used in this paper: SP-A, SP-B, and SP-C, surfactant Volume 86, July 1990, 1-6 proteins, A, B, and C, respectively. Pulmonary Surfactant and Its Apoproteins 1 Type 11 Cell 1* Type I Cell Fluid Surface Air Space Macrophage Figure 1. Schematic diagram of the surfactant system. A single alveolus is shown with the location and movement of surfactant components depicted. Surfactant components are synthesized from precursors (1) in the endoplasmic reticulum (2) and transported via the Golgi apparatus (3) to lamellar bodies (4), which are the intracellular storage granules for surfactant. After secretion into the liquid lining the alveolus, the sur- factant forms tubular myelin (5), which is thought to generate the surface monolayer (6) which lowers surface tension. Subsequently, surfactant components are taken back into type II cells, possibly in the form of small vesicles (7) apparently by a specific pathway involving endosomes (8) and multivesicular bodies (9) and culminating again in storage of surfactant in lamellar bodies. Some surfactant in the liquid layer is also taken up by alveolar macrophages (10). A single transit of the phospholipid components of surfactant through the alveolar lumen normally takes a few hours. The phospholipids in the lumen are taken back into the type II cell and reutilized - 10 times before being degraded. Many of the proline residues in this region are modified by by electron microscopy, the collagenlike region of SP-A is hydroxylation in the 4 position. This modification, presum- - 20 nm long. The six globular heads of the protein appear to ably important for stabilizing the collagenlike triple helix into be held in a roughly circular array, 20 nm in diameter (26). which the amino-terminal one-third of SP-A is assembled (24) The overall plan of SP-A resembles closely the "bunch of appears to be a prerequisite for passage of SP-A through the tulips" organization of complement component Cl q. The secretory apparatus of the cell (25). Human SP-A is also gly- steric relationship of the globular SP-A heads dictated by the cosylated close to the carboxy terminus with a sialylated oligo- collagenlike stems may be important in the interaction be- saccharide chain, but the role of this modification is not tween SP-A and a number of the ligands, including carbohy- known. drates (27), phospholipids (28), and cell-surface receptors The secreted form of SP-A is assembled into a large oligo- (29-31) to which it binds. mer composed of 18 similar subunits with a molecular mass of 700,000 D (24). The active protein is structurally asymmet- Apoprotein B ric with a rodlike amino-terminal stem consisting of six closely Although a small hydrophobic protein was observed in lung associated triple helices, each connected to a globular head surfactant in early experiments (16), it was not until much made up of the carboxy-terminal 150 amino acids. As assessed later that two distinct proteolipids, SP-B and SP-C, were char- 2 S. Hawgood and J. A. Clements acterized in human surfactant (32, 33). These proteolipids and dose response to glucocorticoids suggest that the three (proteins that preferentially extract into organic solvents) are genes may not be regulated in a tightly coordinated fashion associated with the surfactant phospholipids in roughly equal under all conditions (20). abundance. Approximately 1 mg of each proteolipid can be The primary translation product of SP-C mRNA is 197 isolated from 100 mg of surfactant phospholipid. amino acids long (32). Although SP-C is generally assumed to SP-B is synthesized in the type II cell and bronchiolar Clara be a secreted protein, there is no classical amino-terminal cell (18). In human fetal lung the SP-B gene is transcribed leader sequence to direct the precursor into the lumen of the during the second trimester,