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Surfactant metabolism in SP-D gene-targeted mice

December 11, 2018 By Airway Therapeutics

Mice with surfactant protein (SP)-D deficiency have three to four times more surfactant lipids in air spaces and lung tissue than control mice. We measured multiple aspects of surfactant metabolism and function to identify abnormalities resulting from SP-D deficiency. Relative to saturated phosphatidylcholine (Sat PC), SP-A and SP-C were decreased in the alveolar surfactant and the large-aggregate surfactant fraction. Although large-aggregate surfactant from SP-D gene-targeted [(−/−)] mice converted to small-aggregate surfactant more rapidly, surface tension values were comparable to values for surfactant from SP-D wild-type [(+/+)] mice. 125I-SP-D was cleared with a half-life of 7 h from SP-D(−/−) mice vs. 13 h in SP-D(+/+) mice. Although initial incorporation and secretion rates for [3H]palmitic acid and [14C]choline into Sat PC were similar, the labeled Sat PC was lost from the lungs of SP-D(+/+) mice more rapidly than from SP-D(−/−) mice. Clearance rates of intratracheal [3H]dipalmitoylphosphatidylcholine were used to estimate net clearances of Sat PC, which were approximately threefold higher for alveolar and total lung Sat PC in SP-D(−/−) mice than in SP-D(+/+) mice. SP-D deficiency results in multiple abnormalities in surfactant forms and metabolism that cannot be attributed to a single mechanism.

surfactant protein(SP) D is a 43-kDa member of the collectin family of proteins that shares structural homology with SP-A and mannose binding protein (3). In contrast to SP-A, SP-D does not interact with the major surfactant phospholipids and is not associated with lamellar bodies or tubular myelin. Based on in vitro studies, SP-D was thought to be primarily a host defense protein, and there was no direct evidence that SP-D contributed to surfactant function or homeostasis (19). SP-D gene-targeted [(−/−)] mice survive and breed normally under laboratory conditions (2,18); however, their lungs have marked increases in tissue and alveolar surfactant phospholipids. SP-D(−/−) mice also have increased numbers of enlarged foamy alveolar macrophages, changes in the structure of extracellular surfactant, enlarged type II cells with increased lamellar body number and size, and enlarged distal air spaces.

The pool sizes of surfactant lipids and proteins are regulated by the net contributions from synthesis, secretion, uptake and catabolism by macrophages, and reuptake by type II cells that recycle or catabolize surfactant components (35). The factors that influence alveolar and tissue pools of surfactant components are poorly understood. The important role of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling was demonstrated in GM-CSF- and common β-chain receptor-deficient mice that had an alveolar proteinosis characterized by increases in surfactant lipids and proteins, with a selective increase in SP-D (26). Likewise, increased expression of interleukin-4 (IL-4) caused increased surfactant lipid and SP-A, SP-B, and SP-C content in transgenic mice. The largest change in the IL-4 mice was a 90-fold increase in SP-D (10). In contrast, surfactant lipids were markedly increased in the lungs of SP-D(−/−) mice without substantial changes in the amounts of SPs relative to those in wild-type mice (18). To better define the role of SP-D in surfactant homeostasis, we measured SP-A, SP-B, and SP-C, evaluated surfactant forms, and characterized the metabolism of Sat PC and SP-D in SP-D wild-type [(+/+)] and SP-D(−/−) mice in vivo.

Ikegami, M, et al.

Filed Under: Scientific Publications

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