Postnatal adaptation to air breathing necessitates the reduction of surface tension at the air-liquid interface in the alveoli of the lung. The rapid spreading and stability of phospholipids in pulmonary surfactant are mediated by the activity of two hydrophobic proteins, surfactant proteins B and C (SP-B and -C). Deficiency of surfactant proteins is associated with respiratory distress syndrome (RDS) in premature newborn infants, and in adults with adult respiratory distress syndrome (ARDS). While most surfactant deficiencies are secondary to prematurity or lung injury and infection, hereditary surfactant protein B deficiency, caused by mutations in the surfactant protein B gene, was recently identified as an inherited cause of respiratory failure in full-term newborn infants. This chapter describes the pathophysiology and molecular biology of hereditary SP-B deficiency.
STRUCTURE AND FUNCTION OF SURFACTANT PROTEINS
SP-B, a 79-amino-acid amphipathic polypeptide isolated from pulmonary surfactant, is one of four distinct proteins (SP-A, SP-B, SP-C, and SP-D) that are closely associated with surfactant in the airways. SP-A and SP-D are larger, more hydrophilic proteins, and members of the collectin family of calcium-dependent, C-type mammalian lectins (see reference1 for review). SP-A and SP-D are encoded in a gene cluster containing several ancestrally related mammalian lectins on human chromosome 10 (922 to 923).2 Increasing evidence from gene-targeted mice demonstrates a primary role of SP-A (Mr = 32,000–36,000) in host defense.3 SP-A binds and enhances both phagocytosis and killing of various viral and bacterial pathogens (see reference4 for review). SP-D (Mr = 43,000) shares structural features with SP-A and binds various viruses, bacteria, and fungi.5 Evidence from SP-D gene-targeted mice demonstrated a primary role in the regulation of surfactant lipid concentrations.6,7 SP-D gene-targeted SP-D −/− mice also develop emphysema.6
SP-B and SP-C are distinct and structurally unrelated proteins encoded by genes on human chromosome 2 and 8, respectively.8,9 Both hydrophobic proteins were isolated and identified in organic solvent extracts of pulmonary surfactant, and are the major, if not sole, surface active proteins in mammalian surfactant replacement preparations presently used to treat RDS and ARDS in clinical practice. SP-C is a 33- to 34-amino-acid, extremely hydrophobic polypeptide that is produced from a preproprotein of 21,000 to 22,000 daltons.10 The active SP-C peptide is produced only in type II epithelial cells in the lung, and is stored and secreted with surfactant phospholipids and SP-B into the alveolus. SP-C enhances the rate of spreading and stability of phospholipids during the respiratory cycle and is the primary protein component in surfactant replacement preparations such as Survanta® and Curosurf.® While selected deficiency of SP-C has been observed in a number of term infants with respiratory failure,11 a genetic basis of SP-C-related pulmonary disease has not yet been identified.
The 79-amino-acid active SP-B peptide is produced by proteolytic ...