Molecular Biology of the Surfactant Apoproteins

A working knowledge of the pulmonary surfactant proteins has not always been an important tool in the clinician's armamentarium. No inherited or acquired disease resulting from an aberation of these obscure molecules had been described prior to 1993. Over the past 5 years, however, surfactant replacement has become the standard of care for infants with hyaline membrane disease and surfactant therapy trials in adult respiratory distress syndrome have begun. Twenty years of research have yielded a wealth of information about the surfactant proteins, and it is now clear that they are vital to normal respiratory physiology and may be an important component in surfactant therapy. A congenital deficiency of one of the surfactant proteins has been reported to result in neonatal alveolar proteinosis, respiratory failure, and death. The fruits of basic research on the molecular mechanisms of surfactant function have become valuable to the clinician. Early surfactant replacement experiments demonstrated that the intratracheal instillation of the lipid components of surfactant alone were not sufficient to restore normal elastic properties to the detergent-lavaged lungs of animals. These observations were corroborated by pilot studies in human infants, in whom surfactant replacement with dipalmitoyl phosphatidylcholine (DPPC) did not improve gas exchange or pulmonary mechanics. This was a perplexing result, since it had been demonstrated that a monolayer of DPPC harbored nearly all of the surface tension-lowering qualities of isolated surfactant. It is now clear that exogenously administered DPPC is sequestered in rigid multilamellar structures that do not spontaneously form a monolayer under physiological conditions. The nature of the dispersant of whole surfactant that was missing in the DPPC therapy was clarified by Pattle. He noted that the treatment of surfactant bubbles with the protease trypsin greatly reduced their stability. This important observation, which suggested that protein components of surfactant imparted critical biophysical properties to surfactant mixtures, was followed by the discovery of the first of the surfactant proteins, SP-A, by King et al nearly 20 years later. With the application of modern molecular techniques to surfactant biology, three additional surfactant proteins have been reported: SP-B, SP-C, and SP-D. Since the discoveries of these interesting molecules, basic research on surfactant has increasingly focused on the surfactant proteins. The cDNAs for all four proteins have been characterized and the genes for SP-A, SP-B, and SP-C have been sequenced. In vitro experiments of surfactant function have assigned roles to the surfactant proteins in the assembly and maintenance of the alveolar monolayer, in surfactant homeostasis, and in host defense. We now realize that surfactant therapies must include components to enhance the adsorption and spreading of phospholipids at the air—liquid interface. Several surfactant replacement strategies have resulted in a 50% decline in mortality from infant respiratory distress syndrome in large, prospective randomized trials (for review, see Jobe). Both proteinand nonprotein-containing surfactant preparations have proven effective, but mounting evidence suggests that the surfactant proteins have important and unique roles in surfactant function that may enhance the efficacy and scope of surfactant treatment. The clinician who understands the basic functions of surfactant and surfactant proteins is well positioned to identify new applications for these powerful therapies. This review will focus on the genomic structure, transcription, synthesis, and structure—function relationships of the four known surfactant-specific proteins.