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

Clinical Implications

In addition to genetic variability in the SP-A and SP-B genes, several other factors contribute to the pathogenesis of RDS. Therefore, different sets of interactions among these various elements may lead to different phenotypic subgroups as well, as is reflected by the distinct clinical presentations observed (Fig. 9). For example, there is a range of subtle to major variations in the clinical phenotypes -- differences in the severity of disease can be very dramatic. The mechanism that underlies each set of interactions which leads to a different clinical phenotype is likely to be distinct. Therefore, separating the various disease (phenotypic) subgroups, ie, groups I, II, III (as depicted with different geometric shapes in Figure 9), and studying the underlying mechanisms involved will contribute to a better understanding of the pathogenesis in each disease subgroup. This approach can help identify points of therapeutic intervention for each disease subgroup, and may lead to the achievement of nearly 100% success in treatment.

Schematic of complex interplay among factors involved in etiology of putatively distinct phenotypic subtypes (I, II, III) of RDS. Concept adapted from: Floros J, Kala P: Surfactant proteins: Molecular Genetics of neonatal pulmonary diseases. Ann Rev Physiol 60:365-384, 1998.

Figure 9 depicts the influence of multiple sets of interactions (genetic, environment, modifiers) on the phenotype of a disease or a trait with complex etiology. RDS is an example of such disease. In this scenario and in the context of Figure 9, the phenotype of RDS can be viewed in three broad categories (ie, phenotypic subgroups): I) RDS of the prematurely born infant; II) RDS of the infant of the diabetic mother; III) RDS secondary to other problems (ie, meconium aspiration). In the first case, the infant is smaller, is born prematurely, develops RDS soon after delivery, and responds to exogenous surfactant. Radiographic findings are typical of RDS. In the second case, the mother has insulin-dependent diabetes that is poorly controlled, the infant is large, and usually presents organomegaly. The radiograph is dominated by the presence of a large heart. Clinical course is variable and the infant usually responds to surfactant therapy. In the third case, the infant is full-term and there is evidence of multiorgan disease, including surfactant deficiency. Radiograph is atypical (ie, inhomogeneous, not hyperinflated), and surfactant therapy can be used.

Recognizing Disease Subgroups

To identify the various RDS subgroups, genetic markers of unknown or candidate gene loci or clinical markers may be used. A number of genetic markers have been characterized for the SP-B gene[16,18,35] and its flanking regions.[41] SP-B genetic markers as well as other genetic markers (ie, for the other surfactant protein genes) are currently being used to identify RDS subgroups. It is hoped that the use of genetic markers will further facilitate the identification of disease subgroups in each of the three categories of RDS discussed above. For example, the prematurely born infants who develop RDS may consist of infants who may respond to steroid therapy and others who may not. If these two subgroups can be distinguished a priori, ie, with the use of genetic markers, different intervention may be implemented for each subgroup at the start.

Disease subgrouping has facilitated the identification of genetic components for other complex diseases, such as hypertension,[42] where severity was used as a marker for subgrouping, and Alzheimer's,[43,44] where age of onset was used as a marker. In the effort to unravel the complexities of the genetics involved in development of RDS, we are hopeful that genetic and/or clinical markers can be used as tools to identify the various disease subgroups, understand the underlying mechanisms, and identify specific points for therapeutic intervention.

Current Approaches to Treatment

Current therapies for prematurely-born infants at risk of developing RDS include prophylactic surfactant replacement therapy and prenatal maternal corticosteroid treatment. For the most part, prophylactic replacement therapy is best advised for infants of fewer than 28 weeks of gestation, whereas rescue surfactant therapy is recommended for all other prematurely born infants as needed (reviewed in [45]). Prenatal corticosteroid therapy is recommended for women between 24 and 34 weeks of pregnancy who are at risk to deliver prematurely.[46] Corticosteroid therapy acts by accelerating lung maturity - a process that includes enhanced expression of certain surfactant lipid and protein components. Both surfactant replacement therapy and prenatal corticosteroid therapy approaches have led to a significant decrease in infant mortality, have minimized the severity of RDS, and have prevented disease onset altogether. In spite of the success of these therapies, RDS has not been eliminated. Surfactant therapy is primarily administered as a bolus via endotracheal intubation. Other methods (ie, aerosolization) of surfactant administration have also been used.[45] Surfactant therapy seems most effective when given to the prematurely-born infant during the period when the endogenous surfactant system is not yet adequately expressed to allow for levels of surfactant sufficient to prevent alveolar collapse, and can thus spare the infant from respiratory problems. However, surfactant therapy cannot maintain life for prolonged periods in the absence of key endogenous surfactant components. For example, surfactant therapy has failed to maintain indefinitely the life of infants with congenital alveolar proteinosis, where mature SP-B is absent.[47]

To accelerate production of the endogenous surfactant system, scientists have used various hormonal treatments. The use of prenatal steroid therapy represents one such effort. However, because surfactant is a complex of lipid and protein components, and the collective evidence indicates that the different surfactant genes may not be regulated coordinately, the use of various therapies aimed at the acceleration of endogenous surfactant productions should be carefully considered. For example, the expression of the human SP-B gene is enhanced in response to glucocorticoid treatment (reviewed in [24]), whereas the expression of the human SP-A genes is decreased in response to glucocorticoid treatment.[29,35] Moreover, there is evidence to indicate that the level of decreased expression that occurs in response to glucocorticoid treatment differs between the two human SP-A genes and/or alleles.[48,49] Such a lack of coordinate regulation poses challenges and raises a number of questions, such as, when is it appropriate during the course of the disease to use a specific treatment and which infant is likely to benefit when various hormonal or other treatments are used? These challenges concerning therapeutic intervention could be overcome completely or in part if we had a better understanding of the factors involved in disease pathogenesis and the underlying mechanisms in each disease subgroup. Such knowledge will undoubtedly contribute to deciding which therapy is most appropriate for a given phenotypic subgroup. Due to the complexity of the physiological processes, the complexity of RDS etiology, and, most particularly, the complexity of the surfactant system, a more refined, perhaps "custom-made," therapy will most likely become necessary for each disease subgroup if we are to attain nearly 100% efficiency in treatment and/or prevention.

SP-B deficiency is a fatal disease and apart from compassionate care, currently there is no effective treatment available. Lung transplantation has been carried out in a few infants without any long-term results.[50] Gene therapy may be a future treatment for SP-B deficiency. Towards this goal, recent advances in human explant cultures include the targeting to type II and clara cells of reporter genes under the control of human SP-B.[51] Moreover, gene transfer may be possible in the future through fetoscopy late in gestation.[52] Although SP-B deficiency may be amenable to gene therapy,[53] considerably more work is needed before such a therapy becomes a clinical reality.

Another therapy which is in the experimental stage that may prove to be useful in infants where RDS is complicated with pulmonary hypertension is nitric oxide inhalation.[54] Nitric oxide is shown to decrease pulmonary vascular resistance, improve oxygenation, and selectively increase pulmonary dilation in various animal models and pulmonary diseases.[55,54,56,57]

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