Genetic Variability of Surfactant Protein-B and Respiratory Distress Syndrome: Clinical Implications

, Departments of Cellular and Molecular Physiology and Pediatrics; , Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pa.

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In This Article

Background and Physiology

Pulmonary surfactant is a lipoprotein complex that consists of a variety of lipids -- primarily phospholipids -- and several proteins. The function of surfactant is to prevent lung collapse, especially of the terminal liquid-covered airspaces, called alveoli. Within the alveoli, the primary gas exchange units of the lung, oxygen from the atmosphere enters the blood for transport to the peripheral tissues; at the same time carbon dioxide is eliminated from the blood. There are two types of alveolar epithelial cells; type II cells are the more compact variant and are responsible for producing surfactant, which lines the alveoli and differentially reduces surface tension. This allows alveoli of different sizes to exist in functional equilibrium. If the alveoli collapse, the work of breathing (or work to open the alveolus) is increased, resulting in inadequate gas exchange (oxygen/carbon dioxide) that may have fatal consequences.

The alveolus resembles a bubble. The surface of a bubble contracts maximally to form a sphere, and in the process, a pressure is generated that can be predicted by the law of Laplace (P=4T/r; for a sphere with two liquid-gas interfaces). In the alveolus, there is only one liquid-lined surface involved and therefore the numerator becomes 2T rather than 4T (P=2T/r). The pressure (P) increases as the radius (r) of the "bubble" (or the alveolus) decreases. This type of dynamic dictates that the small bubbles/alveoli progressively empty (collapse) into the larger ones (Fig. 1) until the lung becomes one big bubble (sphere). Surfactant prevents this alveolar collapse by lowering the surface tension (T) at the air-liquid interface of the alveolus. As adults we have 300 million alveoli -- each about 1/3mm in diameter. Collectively, they provide the surface area (approximately the size of a tennis court) which is necessary for adequate oxygenation. Therefore, if surfactant were absent and the law of Laplace prevailed, ie, small alveoli progressively collapsing into larger ones, there would be insufficient surface area to provide the oxygenation required for life.

Alveoli with and without surfactant.

Respiratory Distress Syndrome

Because surfactant is produced relatively late in fetal life, an infant born prematurely may have insufficient amounts of surfactant required for normal lung function. These infants will develop respiratory distress syndrome (RDS) because their lungs are totally or partially collapsed. The clinical signs of surfactant deficiency in the prematurely born infant include grunting, tachypnea, retractions, flaring, and need of supplemental oxygen. Pulmonary hypertension may also be part of the clinical picture. Radiographic findings show a bilateral reticulogranular pattern and microscopic examination shows the presence of hyaline membranes lining terminal air spaces. Untreated infants with RDS can either recover and lead a normal (uncompromised) life, subsequently develop chronic problems (ie, bronchopulmonary dysplasia), or succumb to the disease and die.

RDS and Surfactant Deficiency -- The Link

In the 1950s, Dr. Mary Ellen Avery made the clinical correlation between surfactant deficiency in the prematurely-born infant and RDS. She observed at autopsy that the lungs of infants who died from RDS were quite different from the lungs of those who died from other causes. The RDS lungs were red and liver-like, and when the lungs were cut and squeezed, foam or bubbles were not produced at the cut surface, as would be seen in a normal lung or in the lungs of infants who died from nonrespiratory causes. Dr. Avery subsequently showed that the RDS lungs lacked surfactant -- the cellular extracts from the RDS lungs failed to lower surface tension in vitro (a measure commonly used to assess the functional ability of surfactant).[1]

Surfactant Replacement Therapy for RDS

Initial surfactant replacement studies, wherein surfactant therapy was used to treat prematurely-born infants with the hope of minimizing the severity or preventing respiratory problems, were unsuccessful. These studies used lipids "off the laboratory shelf;" therefore, the proteins as well as other components of naturally-derived surfactants were not included in these early surfactant preparations.

It was not until the 1980s that a clinical trial with surfactant was successful.[2] In that study, the surfactant used for therapy was derived from a natural source -- cow lungs -- and therefore contained most of the endogenous surfactant components. In 1989, the FDA licensed a surfactant preparation and surfactant therapy has since been used routinely in nurseries throughout the US. Surfactant therapy and other technological advances have decreased the mortality rate of prematurely-born infants. The mortality rate from RDS has decreased by 30% since the introduction of surfactant therapy in 1989. In recognition of this, The National Heart, Lung, and Blood Institute (NHLBI), in its 50-year celebration of accomplishments, profiled the advances made to save the lives of premature infants through the use of surfactant therapy as one its "success stories."

The encouraging results of that first successful clinical trial in the early '80s were suggestive of an important role for the surfactant proteins in overall surfactant function. This led to a flurry of research activity and, collectively, the findings indicate that the surfactant proteins (relative to the phospholipid components of the surfactant complex) are indeed important in several aspects of surfactant function. A number of studies have shown that surfactant plays a significant role in the regulation of immune cells in the alveolus (reviewed in Phelps [3] ). The predominant surfactant lipids have an inhibitory effect on immune cell function, whereas SP-A, SP-D, and some of the minor lipids (sphingomyelin, PE) have a stimulatory effect. In the normal lung, a delicate balance appears to exist between the inhibition and stimulation of immune cells through the maintenance of an appropriate ratio of the various surfactant components.[4] For example, SP-A exerts a stimulatory effect on macrophage chemotaxis,[5] phagocytosis,[6] oxidant generation,[7] immune cell proliferation,[8] and production of proinflammatory cytokines.[9,10] Surfactant lipids inhibit all of these processes. Moreover, SP-A and SP-B are essential components of tubular myelin, an extracellular form of surfactant, which is thought to be the precursor (ie, gives rise to the active form of surfactant) of the surface layer (reviewed in [11]). Within the epithelial type II cell, surfactant is found in the form of lamellar bodies, onion-like structures. Upon secretion, the lamellar bodies can transform into tubular myelin, a lattice-like structure which is believed to give rise to the active form of surfactant found at the air-liquid interface of the alveolus. Moreover, SP-B as discussed below (physiological importance), is essential for normal lung function. The surfactant proteins include SP-A, SP-B, SP-C, and SP-D. The focus of this review, however, is SP-B, which is encoded by a single gene mapped to chromosome 2.[12]

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