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1Division of Electron Microscopy, Department of Anatomy, University of Göttingen, D-37075 Göttingen, Germany; 2Cardiovascular Research Institute and Department of Pediatrics, University of California San Francisco, San Francisco, California 94118; and 3Stereological Research Laboratory and Electron Microscopy Laboratory, University of Aarhus, DK-8000 Aarhus, Denmark
Submitted 13 April 2004 ; accepted in final form 9 August 2004
Surfactant protein D (SP-D) is a member of the collectin subfamily of C-type lectins, pattern recognition proteins participating in the innate immune response. Gene-targeted mice deficient in SP-D develop abnormalities in surfactant homeostasis, hyperplasia of alveolar epithelial type II cells, and emphysema-like pathology. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is required for terminal differentiation and subsequent activation of alveolar macrophages, including the expression of matrix metalloproteinases and reactive oxygen species, factors thought to contribute to lung remodeling. Type II cells also express the GM-CSF receptor. Thus we hypothesized GM-CSF might mediate some or all of the cellular and structural abnormalities in the lungs of SP-D-deficient mice. To test this, SP-D (D–G+) and GM-CSF (D+G–) single knockout mice as well as double knockout mice deficient for both SP-D and GM-CSF (D–G–) were analyzed by design-based stereology. Compared with wild type, D–G+ as well as D+G– mice showed decreased alveolar numbers, increased alveolar sizes, and decreased alveolar epithelial surface areas. These emphysema-like changes were present to a greater extent in D–G– mice. D–G+ mice developed type II cell hyperplasia and hypertrophy with increased intracellular surfactant pools, whereas D+G– mice had smaller type II cells with decreased intracellular surfactant pools. In contrast to the emphysematous changes, the type II cell alterations were mostly corrected in D–G– mice. These results indicate that GM-CSF-dependent macrophage activity is not necessary for emphysema development in SP-D-deficient mice, but that type II cell metabolism and proliferation are, either directly or indirectly, regulated by GM-CSF in this model.
surfactant protein D; collectins; alveolar macrophages; stereology; granulocyte/macrophage colony-stimulating factor
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