Abstract
SP-C-deficient (SP-C -/-) mice developed a severe pulmonary disorder associated with emphysema, monocytic infiltrates, epithelial cell dysplasia, and atypical accumulations of intracellular lipids in type II epithelial cells and alveolar macrophages. Whereas alveolar and tissue surfactant phospholipid pools were increased, levels of other surfactant proteins were not altered (SP-B) or were modestly increased (SP-A and SP-D). Analysis of pressure-volume curves and forced oscillatory dynamics demonstrated abnormal respiratory mechanics typical of emphysema. Lung disease was progressive, causing weight loss and cardiomegaly. Extensive alveolar remodeling was accompanied by type II cell hyperplasia, obliteration of pulmonary capillaries, and widespread expression of alpha-smooth muscle actin, indicating myofibroblast transformation in the lung parenchyma. Dysplastic epithelial cells lining conducting airways stained intensely for the mucin, MUC5A/C. Tissue concentrations of proinflammatory cytokines were not substantially altered in the SP-C (-/-) mice. Production of matrix metalloproteinases (MMP-2 and MMP-9) was increased in alveolar macrophages from SP-C (-/-) mice. Absence of SP-C caused a severe progressive pulmonary disorder with histologic features consistent with interstitial pneumonitis.
Highlights
SP-C is a 34 –35-amino acid peptide expressed selectively in type II epithelial cells in the alveolus of the lung
A severe pulmonary disorder characterized by emphysema, epithelial cell dysplasia, monocytic cell infiltration, increased ␣-smooth muscle staining, and abnormal lipid accumulations was caused by targeted deletion of the sp-C gene in a congenic strain of SP-C (Ϫ/Ϫ)/129/Sv mice
Heterogeneous pulmonary lesions contained the following: 1) thickened alveolar walls that stained for ␣-smooth muscle actin; 2) extensive monocytic infiltrates and increased expression of metalloproteinases; 3) regions of severe emphysema with septal thinning and degeneration of pulmonary capillaries; 4) epithelial cell dysplasia and MUC5A/C expression in conducting airways; and 5) accumulation of intracellular lipids in various cell types
Summary
SP-C is a 34 –35-amino acid peptide expressed selectively in type II epithelial cells in the alveolus of the lung (for review see Refs. 1 and 2). Biological functions of purified SP-C or synthetic SP-C peptides are highly active in vitro and in vivo, enhancing surfactant properties of lipids and restoring lung function in surfactant-deficient animals [6, 7] These results indicate that SP-C plays an important role in the spreading and stabilization of phospholipid films in the alveolus. An unexpected role for SP-C in pulmonary homeostasis was provided by recent studies [8, 9] demonstrating that a mutation in the sp-C gene was associated with idiopathic interstitial pneumonitis (IIP) in humans. Pulmonary disease in these patients was inherited as an autosomal dominant trait. SP-Cdeficient mice developed severe, progressive pulmonary disease associated with emphysema, ␣-smooth muscle actin staining, monocytic infiltrates, and epithelial cell dysplasia in conducting and peripheral airways
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