Surfactant protein B: unambiguously necessary for adult pulmonary function.

IN THE REPORT FROM MELTON ET AL., one of the current articles in focus (Ref. 21, see p. L543 in this issue), they use genetically engineered mice to demonstrate that at least 25% of normal surfactant protein B production is required for adult pulmonary function. With the use of doxycycline-regulated, compound-conditional knockout murine lineages, the authors show that genetic disruption of surfactant protein B synthesis causes adult respiratory failure due to loss of surface activity of the pulmonary surfactant. This observation suggests a method for stratification of adult respiratory failure phenotypes based on surfactant protein B quantity and function and provides additional rationale for treatment of adult respiratory failure with surfactant replacement. The evolutionary conservation of surfactant protein B supports its unambiguous requirement for adult pulmonary function demonstrated by Melton et al. Experience in newborn infants with surfactant replacement therapy and with surfactant protein B deficiency provides lessons to shape these strategies. The pulmonary surfactant system, a complex mixture of lipid and protein, evolved when vertebrates began air breathing between 320 and 420 million years ago (5). Fossil records suggest a common, air-breathing ancestor for all vertebrates (6). In nonmammals, especially those without diaphragms, the pulmonary surfactant likely functions as an antiadhesive to ensure reexpansion of large gas-exchanging units (faveoli) after compression by forces like birth or ingestion of a relatively large food source (5). In mammals, the pulmonary surfactant is required for maintenance of the lung’s gas-containing, aqueous-lined alveoli and minimization of work of breathing during regular volume changes (5). The striking evolutionary conservation of surfactant protein B is demonstrated by studies of the Australian lungfish Neoceratodus forsteri, one of the most primitive surviving air-breathing vertebrates: antibodies to human surfactant protein B identify surfactant protein B-like peptides in lamellar body-like organelles of pulmonary epithelium in this species (26). Structural similarities between surfactant protein B and other members of the amoebapore superfamily suggest that its function in these early vertebrates may have been antimicrobial (1, 31). However, its conservation during mammalian evolution is likely due to its unique and irreplaceable role in the surface activity of the pulmonary surfactant of air-breathing mammals. Among the four known surfactant-associated proteins (A, B, C, and D), surfactant protein B is unique in evolutionary and functional characteristics. Although similar in hydrophobicity and surface activity to surfactant protein C (29, 30), surfactant protein B probably arose considerably earlier in evolution than surfactant protein C. Unlike the hydrophilic surfactant proteins A (also detectable early in pulmonary evolution) and D, surfactant protein B is surface active: it contains 5 amphiphilic -helices that interact with the surfactant lipid monolayer to reduce breakup of anionic lipid headgroups during the folding transition of the pulmonary surfactant’s phospholipid monolayer and loss of these same headgroups to the subphase upon monolayer collapse (10, 19). Surfactant protein B also lowers surface tension by disrupting attractive forces between water molecules (19). The evolutionary conservation of surfactant protein B and its surface tension-lowering characteristics in air-breathing mammals both predict a critical role in adult lung function. Melton et al. (21) confirm this prediction in mice. Clinical experience with newborn infants provides evidence of the potential benefits and limitations of using surfactant protein B in evaluation and treatment of adults with respiratory failure. After pioneering work by von Neergard, Pattle, and Clements (reviewed in Ref. 10), Avery and Mead first reported the importance of the pulmonary surfactant for successful fetal-neonatal pulmonary transition in 1959 (3). With the use of a Langmuir-Wilhelmy balance to compare surface tension-lowering capacity of saline extracts of lungs from premature infants who had died of hyaline membrane disease and more mature infants who died from other causes, they showed that lungs of premature infants lacked surface-active material and thus established the biochemical defect that accounts for significant pulmonary mortality and morbidity in prematurely born infants. Further studies by Gluck et al., Klaus et al., and King and Clements (reviewed in Ref. 10) led to recognition of the importance of disaturated phospholipid (specifically, dipalmitoyl phosphatidylcholine) for function of the pulmonary surfactant and identification of four surfactant-associated proteins (A, B, C, and D). In 1980, Fujiwara et al. reported the initial uncontrolled trial of bovine surfactant replacement in prematurely born human infants with severe respiratory failure that suggested the efficacy of this approach (7). Subsequently, several large studies Address for reprint requests and other correspondence: F. Sessions Cole, Division of Newborn Medicine, St. Louis Children’s Hospital, One Children’s Place, St. Louis, Missouri 63110 (E-mail address: [email protected]). Am J Physiol Lung Cell Mol Physiol 285: L540–L542, 2003; 10.1152/ajplung.00111.2003.