Clinical biological and genetic heterogeneity of the inborn errors of pulmonary surfactant metabolism

Pulmonary surfactant is a multimolecular complex located at the air-water i nterface within the alveolus to which a range of physical (surface-active p roperties) and immune functions has been assigned. This complex consists of a surface-active lipid layer (consisting mainly of phospholipids), and of an aqueous subphase. From discrete surfactant sub-fractions one can isolate strongly hydrophobic surf acta nt proteins B (SP-B) and C (SP-C) as well a s collectins SP-A and SP-D, which were shown to have specific structural, m etabolic, or immune properties. Inborn or acquired abnormalities of the sur factant, qualitative or quantitative in nature, account for a number of hum an diseases. Beside hyaline membrane disease of the preterm neonate, a clus ter of hereditary or acquired lung diseases has been characterized by perio dic acid-Schiff-positive material filling the alveoli. From this heterogene ous nosologic group, at least two discrete entities presently emerge. The f irst is the SP-B deficiency, in which an essentially proteinaceous material is stored within the alveoli, and which represents an autosomal recessive Mendelian entity linked to the SFTPB gene (MIM 1786640). The disease usuall y generally entails neonatal respiratory distress with rapid fatal outcome, although partial or transient deficiencies have also been observed. The se cond is alveolar proteinosis, characterized by the storage of a mixed prote in and lipid material, which constitutes a relatively heterogeneous clinica l and biological syndrome, especially with regard to age at onset (from the neonate through to adulthood) as well as the severity of associated signs. Murine models, with a targeted mutation of the gene encoding granulocyte m acrophage colony-stimulating factor (GM-CSF) (Csfgm) or the beta subunit of its receptor (II3rb1) support the hypothesis of an abnormality of surfacta nt turnover in which the alveolar macrophage is a key player. Apart from SP -B deficiency, in which a near-consensus diagnostic chart can be designed, the ascertainment of other abnormalities of surfactant metabolism is not st raightforward. The disentanglement of this disease cluster is however essen tial to propose specific therapeutic procedures: repeated broncho-alveolar ravages, GM-CSF replacement, bone marrow grafting or lung transplantation.