Abstract
BackgroundSurfactant protein D (SP-D) deficient mice develop emphysema-like pathology associated with focal accumulations of foamy alveolar macrophages, an excess of surfactant phospholipids in the alveolar space and both hypertrophy and hyperplasia of alveolar type II cells. These findings are associated with a chronic inflammatory state. Treatment of SP-D deficient mice with a truncated recombinant fragment of human SP-D (rfhSP-D) has been shown to decrease the lipidosis and alveolar macrophage accumulation as well as production of proinflammatory chemokines. The aim of this study was to investigate if rfhSP-D treatment reduces the structural abnormalities in parenchymal architecture and type II cells characteristic of SP-D deficiency.MethodsSP-D knock-out mice, aged 3 weeks, 6 weeks and 9 weeks were treated with rfhSP-D for 9, 6 and 3 weeks, respectively. All mice were sacrificed at age 12 weeks and compared to both PBS treated SP-D deficient and wild-type groups. Lung structure was quantified by design-based stereology at the light and electron microscopic level. Emphasis was put on quantification of emphysema, type II cell changes and intracellular surfactant. Data were analysed with two sided non-parametric Mann-Whitney U-test.Main ResultsAfter 3 weeks of treatment, alveolar number was higher and mean alveolar size was smaller compared to saline-treated SP-D knock-out controls. There was no significant difference concerning these indices of pulmonary emphysema within rfhSP-D treated groups. Type II cell number and size were smaller as a consequence of treatment. The total volume of lamellar bodies per type II cell and per lung was smaller after 6 weeks of treatment.ConclusionTreatment of SP-D deficient mice with rfhSP-D leads to a reduction in the degree of emphysema and a correction of type II cell hyperplasia and hypertrophy. This supports the concept that rfhSP-D might become a therapeutic option in diseases that are characterized by decreased SP-D levels in the lung.
Highlights
Surfactant protein D (SP-D) deficient mice develop emphysema-like pathology associated with focal accumulations of foamy alveolar macrophages, an excess of surfactant phospholipids in the alveolar space and both hypertrophy and hyperplasia of alveolar type II cells
We have previously reported that a considerable number of apoptotic and necrotic alveolar macrophages are present in the bronchoalveolar lavage (BAL) in SP-D knock-out mice [11] and have postulated that delayed clearance of dead and dying cells may be involved in generating a chronic inflammatory state which leads to emphysema [12,13,14,15]
Light and electron microscopy The parenchymal architecture of the knock-out mice that were not treated with recombinant fragment of human SP-D (rfhSP-D) but with PBS demonstrated typical features of SP-D-deficiency: the distal airspace was enlarged and there were focal accumulations of foamy alveolar macrophages in the peri-bronchial and sub-pleural regions (Fig. 1A)
Summary
Surfactant protein D (SP-D) deficient mice develop emphysema-like pathology associated with focal accumulations of foamy alveolar macrophages, an excess of surfactant phospholipids in the alveolar space and both hypertrophy and hyperplasia of alveolar type II cells. These findings are associated with a chronic inflammatory state. The lungs of mice deficient in SP-D exhibit hypertrophy and hyperplasia of type II cells, a diminished number of alveoli, increased alveolar size and decreased alveolar surface area [9]. In addition to the increased intra-alveolar surfactant pool, stereological analysis revealed an increased intracellular surfactant pool [9]
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