Surfactant protein D (SP-D) is a 43-kDa member of the collectin family of collagenous lectin domain-containing proteins that is expressed in epithelial cells of the lung. The SP-D gene was targeted by homologous recombination in embryonic stem cells that were used to produce SP-D (6) and SP-D (2/2) mice. Both SP-D (2/2) and SP-D (6) mice survived normally in the perinatal and postnatal periods. Whereas no abnormalities were observed in SP-D (6) mice, alveolar and tissue phosphatidylcholine pool sizes were markedly increased in SP-D (2/2) mice. Increased numbers of large foamy alveolar macrophages and enlarged alveoli were also observed in SP-D (2/2) mice. Phospholipid composition was unaltered in SP-D (2/2) mice, but surfactant morphology was abnormal, consisting of dense phospholipid membranous arrays with decreased tubular myelin. The pulmonary lipoidosis in the SP-D (2/2) mice was not associated with accumulation of surfactant proteins B or C, or their mRNAs, distinguishing the disorder from alveolar proteinosis syndromes. Surfactant protein A mRNA was reduced and, SP-A protein appeared to be reduced in SP-D (2/2) compared with wild type mice. Targeting of the mouse SP-D gene caused accumulation of surfactant lipid and altered phospholipid structures, demonstrating a previously unsuspected role for SP-D in surfactant lipid homeostasis in vivo.
Pulmonary surfactant is essential for normal lung mechanics and gas exchange in the lung. Both quantitative and qualitative deficiencies in pulmonary surfactant are associated with neonatal respiratory distress (1), adult respiratory distress syndrome (2), and congenital deficiencies of surfactant protein B (3), demonstrating the important clinical consequences of abnormalities in surfactant. Alveolar surfactant pools are regulated at multiple levels including intracellular synthesis, secretion, re-uptake of lipids and proteins by type II epithelial cells, and the uptake and degradation of these components by alveolar macrophages (4). The synthesis and clearance of surfactant phospholipids and proteins is further influenced by developmental, mechanical, and humoral stimuli that serve to maintain steady-state surfactant concentrations after birth (1). Recent studies demonstrated the important role of surfactant catabolism in determining steady-state surfactant protein and lipid concentrations in the lung. Deficiency of granulocyte macrophage colony stimulating factor (GM-CSF)1 or GM-CSF receptors are both associated with extracellular accumulation of pulmonary surfactant lipids and proteins, causing pulmonary alveolar proteinosis both in transgenic mice and in humans (3, 5–7). Mechanisms selectively regulating lipid concentrations have not been identified, and a role for SP-D in regulating surfactant has not been previously reported. In vitro studies support the concept that surfactant proteins may be important in the regulation of surfactant homeostasis (8). Although the hydrophobic surfactant proteins SP-B and SP-C have roles in production of the surfactant monolayer, in vitro studies indicated that surfactant proteins A, B, and C may also facilitate surfactant uptake and/or secretion by type II epithelial cells (8). However, recent studies of SP-A null mice have not supported the primary role of surfactant protein A in surfactant secretion or re-uptake. The absence of SP-A does not lead to obvious physiologic or morphologic structural abnormalities of the lung. SP-A null mutant mice lack tubular myelin figures but produce highly functional surfactant that adsorbs rapidly and produces stable monolayers. Surfactant lipid synthesis, secretion, and re-uptake were essentially normal in SP-A null mice (9–11). In contrast, targeted deletion of SP-B caused abnormal processing of proSP-C, the absence of tubular myelin, and death from respiratory failure in neonatal SP-B (2/2) mice (12).
Korfhagen, TR, et al.
The Journal of Biological Chemistry 1998
