Clinical Biological and Genetic Heterogeneity of the Inborn Errors of Pulmonary Surfactant Metabolism

Abstract

Pulmonary surfactant is a multimolecular complex located at the air-water interface within the alveolus to which a range of physical (surface-active propert i e s ) 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 surfactant proteins B (SP-B) and C (SP-C) as well as collectins SP-A and SP-D, which were shown to have specific structural, metabolic, or immune properties. Inborn or acquired abnormalities of the s u rfactant, qualitative or quantitative in nature, account for a number of human diseases. Beside hyaline membrane disease of the preterm neonate, a cluster of hereditary or acquired lung diseases has been characterized by periodic acid-Schiff-positive material filling the alveoli. From this heterogeneous nosologic group, at least two discrete entities presently emerge. The first 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 S F T P B gene (MIM 1786640). The disease usually generally entails neonatal respiratory distress with rapid fatal outcome, although partial or transient deficiencies have also been observed. The second is alveolar proteinosis, characterized by the storage of a mixed protein and lipid material, which constitutes a relatively heterogeneous clinical 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 macrophage colonystimulating factor (GM-CSF) (C s f g m) or the ␤ subunit of its receptor (I l 3 r b 1) support the hypothesis of an abnormality of surfactant 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 straightforward. The disentanglement of this disease cluster is however essential to propose specific therapeutic procedures: repeated broncho-alveolar lavages, GM-CSF replacement, bone marrow grafting or lung transplantation.

Pulmonary Alveolar Proteinosis and tuberculosis in a diabetic patient: a rare or a seldom diagnosed association

“…A recent study [28], in which the concentration of the surfactant apoprotein (SP-A) was measured in the amniotic liquid of pregnant diabetics (n=29) and non-diabetic pregnant women (n=358), revealed that its level is directly proportional to the time of pregnancy (less than 3 mg/mL between the 30 It has been shown that laboratory rats with deficiency of the gene that codifies the GM-CSF produce an abnormal accumulation of surfactant, similar to that seen in humans with PAP [29]. Experimental models, designed primarily for the study of hematopoiesis in rats, suggest that mutations of the gene that codifies GM-CSF [42] or of the beta subunit of its receptor (I13rb1) [44] may stimulate metabolic alterations in the surfactant, which are responsible for PAP [31,42]. There is incipient evidence that seems to demonstrate that daily replacement of GM-CSF (3-9µg/kg/day) during 12 weeks, in PAP patients, stimulates clinical, radiological and functional improvement, without repercussions in the WBC count [45].…”

An Official American Thoracic Society Clinical Practice Guideline: Classification, Evaluation, and Management of Childhood Interstitial Lung Disease in Infancy

“…Findings consistent with pulmonary alveolar proteinosis should lead to an investigation of surfactant dysfunction mutations, GM-CSF pathway abnormalities, and lysinuric protein intolerance (80,(88)(89)(90)(91)(92)(93)(94)(95). Evidence of aspiration may be obtained by lipid staining of alveolar macrophages (96), although the sensitivity and specificity of the finding is questionable (97,98).…”

Task force on chronic interstitial lung disease in immunocompetent children

“…BAL is diagnostic for pulmonary alveolar proteinosis, which is characterised by milky appearing fluid, abundant extracellular and intra-macrophage proteinaceous periodic acid-Schiff-positive material, and presence of foamy alveolar macrophages (AM), [41]. Other investigations that can be proposed are studies of various surfactant components, phospholipids and apoproteins [44]. BAL can also be diagnostic for pulmonary alveolar haemorrhage.…”