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Pulmonary surfactant is a lipoproteinaceous substance that normally comprises a thin film lining alveoli, where it functions to reduce surface tension, thereby preventing alveolar collapse and leakage of capillary fluid into the alveolar lumen. It is composed of mostly polar phospholipids (∼85%) with smaller amounts of neutral lipids (∼5%, mostly cholesterol) and proteins (∼10%, surfactant protein [SP]-A, SP-B, SP-C, and SP-D). SP-B and SP-C are surface active, whereas SP-A and SP-D are members of the collectin family, part of host innate immunity. Surfactant lipids and proteins both contribute to its surface tension–lowering properties, and surfactant proteins also participate in regulation of surfactant metabolism, microbial pathogen clearance, and regulation of alveolar macrophage functions.

Surfactant homeostasis is critical to alveolar function, and both the quantity and composition of surfactant are strictly maintained by mechanisms resulting in balanced production and clearance (Fig. 511-1). Surfactant lipids and proteins are synthesized in alveolar type II epithelial cells, secreted into the alveolar lumen, and removed by recycling and catabolism in alveolar macrophages. Clearance of surfactant by alveolar macrophages requires stimulation by granulocyte-macrophage colony-stimulating factor (GM-CSF) in the lungs. GM-CSF also stimulates the host defense functions of both macrophages and neutrophils.

Figure 511-1

Normal regulation of surfactant homeostasis. Surfactant lipids and proteins are produced in and secreted from the alveolar type II epithelial cell. Surfactant is then cleared by either the alveolar type II epithelial cell, where it is recycled or catabolized by the alveolar macrophage. Disruptions in surfactant homeostasis by either disorders of surfactant production, caused by mutations in SFTPB, SFTPC, ABCA3, or NKX2.1, or disorders of surfactant clearance and disruption in granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling by GM-CSF autoantibodies of mutations in the GM-CSF receptor lead to pulmonary alveolar proteinosis (PAP) syndrome.

Disruption of surfactant homeostasis can cause pulmonary alveolar proteinosis (PAP), a syndrome occurring in a heterogeneous group of rare diseases defined by a common pathologic feature—excessive accumulation of intra-alveolar surfactant, which results in dyspnea, impaired oxygen uptake, and hypoxemic respiratory failure. Some PAP-causing disorders are also associated with abnormal lung development and/or fibrosis (due to abnormal surfactant composition) whereas others are associated primarily with increased surfactant accumulation and infection risk (due to impairment of GM-CSF–dependent functions). Clinical presentation and treatment options both correlate to some degree with these subgroupings. Consequently, these diseases can be usefully divided into disorders of surfactant production or surfactant clearance (Table 511-1). In this chapter, we describe current knowledge on the pathogenesis, epidemiology, clinical presentation, therapy, and prognosis of these diseases.


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