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(American Journal of Pathology. 2005;167:1267-1277.)
© 2005 American Society for Investigative Pathology

Increased and Prolonged Pulmonary Fibrosis in Surfactant Protein C-Deficient Mice Following Intratracheal Bleomycin

William E. Lawson^*, Vasiliy V. Polosukhin^*, Georgios T. Stathopoulos^*, Ornella Zoia^*, Wei Han^*, Kirk B. Lane^*, Bo Li^*, Edwin F. Donnelly, George E. Holburn, Kenneth G. Lewis, Robert D. Collins, William M. Hull^¶, Stephan W. Glasser^¶, Jeffrey A. Whitsett^¶ and Timothy S. Blackwell^*||

From the Department of Medicine,^* Division of Allergy, Pulmonary, and Critical Care Medicine, and the Departments of Radiology and Radiological Sciences, Pathology, and Cell and Developmental Biology,|| Vanderbilt University School of Medicine, Nashville, Tennessee; the Department of Veterans Affairs Medical Center, Nashville, Tennessee; and the Division of Pulmonary Biology,^¶ Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio

Recent reports have linked mutations in the surfactant protein C gene (SFTPC) to familial forms of pulmonary fibrosis, but it is uncertain whether deficiency of mature SP-C contributes to disease pathogenesis. In this study, we evaluated bleomycin-induced lung fibrosis in mice with genetic deletion of SFTPC. Compared with wild-type (SFTPC+/+) controls, mice lacking surfactant protein C (SFTPC–/–) had greater lung neutrophil influx at 1 week after intratracheal bleomycin, greater weight loss during the first 2 weeks, and increased mortality. At 3 and 6 weeks after bleomycin, lungs from SFTPC–/– mice had increased fibroblast numbers, augmented collagen accumulation, and greater parenchymal distortion. Furthermore, resolution of fibrosis was delayed. Although remodeling was near complete in SFTPC+/+ mice by 6 weeks, SFTPC–/– mice did not return to baseline until 9 weeks after bleomycin. By terminal dUTP nick-end labeling staining, widespread cell injury was observed in SFTPC–/– and SFTPC+/+ mice 1 week after bleomycin; however, ongoing apoptosis of epithelial and interstitial cells occurred in lungs of SFTPC–/– mice, but not SFTPC+/+ mice, 6 weeks after bleomycin. Thus, SP-C functions to limit lung inflammation, inhibit collagen accumulation, and restore normal lung structure after bleomycin.

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